1,5-diphenyl-3-formazancarbonitril parasiticides

ABSTRACT

The present invention is directed to the use of 1,5-diaryl-3 -formazancarbonitrile compounds for the control of parasites in vertebrate animals.

CROSS REFERENCE TO RELATED APPLICATION

This is a continuation-in-part of my copending application Ser. No.07/792,111, filed Nov. 14, 1991, and abandoned after present applicationwas filed.

BACKGROUND OF THE INVENTION

By definition, a parasite is an organism which lives on, and typicallyat the expense of, another organism called the "host." Parasiticorganisms are found in many different phyla of the animal world, andhosts are similarly found in many different phyla of the animal world.The greatest number of parasites are members of the phyla

Platyhelminthes, the Classes Trematoda and Cestoidea;

Nematoda; and

Arthropoda, the Classes Arachnida and Insecta.

The Platyhelminthes and Nematoda are informally referred to as"helminths." These species typically live in the intestinal tract, or insome cases other internal organs, of the host; these species are oftencalled "endoparasites." The arthropod parasites are often called"ectoparasites" because they typically attack the host on its external("ecto") surface. Agents which control both internal and externalparasites are sometimes referred to as "endectocides."

The hosts are typically vertebrates. Human beings are of coursepotential hosts for many parasites, and in tropical areas and in areaswith minimal sanitation, parasitic infections are a regular part ofmedical practice. Also highly subject to attack by parasites are thenumerous livestock animals such as cattle, sheep, pigs, goats, chickens,turkeys, ducks, geese, and the like. Likewise, horses are subject toparasitic attack, as are mink and other animals grown for their fur; andrats, mice and other animals used in laboratory and research settings.Companion animals such as dogs and cats are highly subject to attack byparasites, and because of their close relationship with humans, suchparasitism poses problems for the humans with whom they are associated.Fish and other animals grown in aquaculture are also subject toparasitic attack. In short, parasitism involves essentially the wholerange of vertebrate animals. Further, parasitic organisms have evolvedmany quite specific modes of interaction with their hosts, which makesthem relatively inaccessible to control. Many of them live internallywithin the host; and in this and other ways, they have ingeniouslyavoided control.

The economic toll from parasite infestation is staggering. In thelivestock realm, animals suffer reduced feed efficiency and growthrates. Milk and wool production suffer; and there is damage to fleece,hides, and pelts. Animals are rendered susceptible to secondarymicrobiological infections and to further parasite attack. Notinfrequently, parasite attack is fatal. It also causes discomfort evenwhen it is not severely detrimental to the host. Although a number ofparasiticides are in use, they suffer from a variety of problems,including a limited spectrum of activity, the need for repeatedtreatment, and, in many instances, resistance by parasites. Therefore,there is a critical need for new parasiticides.

The present invention provides a new tool in the control of parasiticorganisms, especially those "hematophagous" organisms which attack theirhosts by ingesting blood. By "ingesting" is meant not only thoseparasites which pierce and suck the blood from a circulatory system, butalso those parasites, typically arthropods, which consume tissue of thehost and thereby inevitably consume blood. This new tool is a class ofcompounds known as formazans. Many of the compounds are old, see U.S.Pat. No. 4,069,320. This patent describes the subject compounds asuseful in controlling insects, and as noted above, there are parasiticorganisms among the insects. However, the teaching of U.S. Pat. No.4,069,320 is that insects can be controlled by contact, a techniquewhich, however successful, is inherently impractical or impossible as atool to control blood-ingesting parasitic organisms. Only a method ofachieving systemic control via the circulatory system of the host canprovide truly effective control of blood-ingesting parasitic organisms,and there is nothing in U.S. Pat. No. 4,069,320, which suggests orteaches any way of providing such systemic control. Thus, the presentdiscovery unexpectedly provides a new tool in the control of parasiticorganisms.

BRIEF SUMMARY OF THE INVENTION

The present invention is directed to the prevention of parasitic attackon host animals.

In more detail, the present invention is directed primarily to a methodfor protecting a vertebrate animal against a blood-ingesting parasitewhich comprises administering to the animal an effective amount of anactive agent which is a compound of the formula: ##STR1## wherein each Rindependently represents a moiety of the formula: ##STR2## wherein R¹ iscyano;

R² is nitro;

R³ is bromo, chloro, or fluoro;

R⁴ is iodo or a group of the formula --R⁵ _(n) R⁶ wherein n represents 0or 1, R⁵ represents

--O--,

--S--,

--SO--,

--SO₂, or

--OSO₂ --, and

R⁶ represents

--CF₃,

--CF₂ CF₂ H,

--CH₂ CF₃, or

--C₂ F₅ ;

with the following limitations:

(1) at least one R bears at least one substituent,

(2) when an R contains one or more R¹, R², or R⁴ substituents, the totalnumber of substituents on that R is not more than 3; or aphysiologically acceptable salt thereof.

Although the primary method of the present invention, set forth above,is that of protecting a vertebrate against blood-ingesting parasites,other methods are also included within the scope of the presentinvention. One other method is that of administering to a vertebrateanimal an effective amount of the same active agent as above defined, toprotect against attack by non-blood-ingesting intestinal parasites.These are parasites which live in the intestinal tract, with or withoutattachment, and ingest the contents of the intestinal tract. Examplesinclude Trichostrongylus, Nematodirus, and tapeworm. The presentcompounds are also useful in a yet other method, in which the sameactive agent as above defined, is employed as a "feed throughlarvicide." In this method, the compound is administered to a vertebrateanimal, especially a warm blooded animal, in order to inhibit parasiticorganisms which live in the feces of the animal. Such organisms aretypically insect species in the egg or larval stage.

The present invention is also directed to methods employing, andcompositions comprising, the combination of (1) a compound of Formula Iand (2) a known parasiticide. Preferred known parasiticides for suchcombinations are the following:

albendazole,

fenbendazole,

flubendazole,

mebendazole,

oxfendazole,

oxibendazole,

ricobendazole,

thiabendazole, and

triclabendazole;

and the following:

levamisole,

morantel,

pyrantel, and

piperazine,

or a physiologically acceptable salt of this latter group. Suchcompositions allow enhanced control of parasites.

In addition to the foregoing novel methods, the present invention isdirected to certain novel compounds. These are (1) the compounds ofFormula I wherein at least one of R bears an --R⁵ _(n) R⁶ substituentwherein n is 1 and R⁵ is --OSO₂ --; (2) the quaternary ammonium salts ofall of the compounds defined by Formula I, wherein the salt moiety is ofthe formula ##STR3## wherein each R⁷ is independently selected from thegroup consisting of alkyl of from 1 to 20 carbon atoms, with the totalnumber of carbon atoms in all of the R⁷ groups being from 4 to 40; and(3) the salts of the compounds defined by Formula I with a known basicparasiticidal compound selected from the group consisting of

levamisole,

morantel,

pyrantel, and

piperazine.

Yet other embodiments will be apparent from the following detaileddescription of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The compounds to be employed in the present invention are definedthroughout by the following formula: ##STR4## However, as noted in U.S.Pat. No. 4,069,320, the compounds exist as tautomers of the above andtwo other forms: ##STR5## For consistency, the first of these three isused throughout, but it is to be understood that it designates any ofthe forms or a mixture of any of them. Cis and trans or syn and antiisomers are also possible and are also included in the single formulaused throughout.

The compounds are prepared by known techniques, which are well describedin U.S. Pat. No. 4,069,320, which is incorporated herein by reference.There is also a general review article on formazans: Chem. Reviews,55,355-483 (1955). For the convenience of the reader, the principalsynthetic technique is summarized below.

An aniline of the formula

    R-NH.sub.2

is diazotized by reacting it with a nitrosating agent in a stronglyacidic medium at a temperature of from -20° to 100° C., typically 0°-40°C.

The resulting diazonium salt

    R-N.sup.+.sub.2 X.sup.-

wherein X is Cl⁻, HSO⁻ ₄, H₂ PO⁻ ₄ or other counter ion from the acid,is then coupled with an active methylene compound of the formula

    CN-CH.sub.2 -CONH.sub.2

in an aqueous media at temperatures of from -20° to 100° C., andpreferably at temperatures of 0° to 40° C.

The reaction initially yields a hydrazone intermediate: ##STR6## whichcan be isolated at pH of preferably 4-6. However, when a symmetricalcompound is desired, one mole of the active methylene compound isemployed per two moles of diazonium salt, and the final product can beobtained and isolated directly at pH of 4 to 12. When an asymmetricalcompound is desired, equimolar amounts of a first diazonium salt andactive methylene compound are used, and the hydrazone intermediate, withor without isolation, is reacted with a different diazonium salt.

Salts are prepared in standard procedures. Typically the formazan isreacted with a metal or ammonium hydroxide, or in the instance of saltswith known basic parasiticidal compounds, with the particularcompound--in either instance, in a suitable solvent.

The quaternary ammonium salts of the present invention: ##STR7## arenovel. They are prepared by reacting the parent formazan ##STR8## with aquaternary ammonium hydroxide of the formula ##STR9## The reaction iscarried out in a reaction medium, typically water, and at temperaturesover a wide range, conveniently at room temperature. The salt typicallyprecipitates and is recovered by filtration.

The quaternary ammonium salts are also prepared by an alternatesynthetic route. In this route, the same active methylene compounddescribed above is reacted with a quaternary ammonium hydroxide of theformula ##STR10## to obtain a compound of the formula ##STR11## whichcan be isolated but is typically reacted in situ with a diazonium salt,or sequentially with two different diazonium salts when an asymmetricalproduct is desired. The reaction yields the desired formazan quaternaryammonium salt directly. Reaction conditions are otherwise the same asdescribed above.

The following syntheses are reported for illustrative purposes.

Symmetrical Formazan

1,5-Bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile was preparedas follows:

Sodium nitrite (2.36 grams; 0.34 mole) in 5 ml of water was added slowlyto 4-(trifluoromethyl)aniline (5.00 grams; 0.031 mole) in 45 ml of 3NHCl at 0°-5° C. 2-Cyanoacetamide (1.30 gram; 0.015 mole) in about 25 mlof water was added dropwise. The reaction mixture was stirred 20minutes, filtered, and added dropwise to sodium acetate (22.88 grams;0.279 mole) in 150 ml of water at room temperature. The reaction mixturewas stirred overnight. The product precipitated and was recovered andrecrystallized from methanol, yield 2.5 grams, m.p. 234°-236° C.

Asymmetrical Formazan

1-(4-(Trifluoromethyl)phenyl)-5-(4-(trifluoromethylsulfonyloxy)phenyl)-3-formazancarbonitrilewas prepared as follows:

Sodium nitrite (0.94 grams; 0.0137 mole) in 2 ml of water was addedslowly to p-(trifluoromethyl)aniline (2.0 gram; 0.0124 mole) in 20 ml of2N HCl. 2-Cyanoacetamide (0.52 gram; 0.062 mole) in ˜20 ml of water wasnext added. The reaction mixture was stirred 30 minutes, filtered, andadded dropwise at room temperature to sodium acetate (9.17 gm; 0.1118mole) in 100 ml of acetic acid. The reaction mixture was stirred 2 hoursat room temperature, yielding a precipitate which was separated byfiltration and determined to be the desired intermediate,2-cyano-((4-(trifluoromethyl)phenyl)hydrazono)acetamide, m.p., 225°-227°C.

4-(Trifluoromethylsulfonyloxy)aniline (1.2 gram; 0.005 mole) in 15 ml of2N HCl was mixed with sodium nitrite (470 mg) at 0°-5° C. This was thenadded to a solution of the intermediate,2-cyano-((4-(trifluoromethyl)phenyl)hydrazono)acetamide, in 250 ml ofmethanol with 5 grams of sodium acetate dissolved in it. The reactionmixture was stirred for 2-3 hours, cooled, and filtered to separate theprecipitated solid. TLC showed three spots, and the material waschromatographed using initially 25% methylene chloride/hexane,increasing to 50% methylene chloride for the last band. Three productswere obtained, two symmetrical formazans:

1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile, m.p.,235°-237° C.

1,5-bis(4-trifluoromethylsulfonyloxy)phenyl)-3-formazancarbonitrile,m.p., 189°-191° C. and the desired asymmetrical formazan:

1-(4-trifluoromethyl)phenyl)-5-(4-trifluoromethylsulfonyloxy)phenyl)-3-formazancarbonitrile,m.p., 182°-184° C.

Salt

The sodium salt of 1,5-bis(3,4-dichlorophenyl)-3-formazancarbonitrilewas prepared as follows.

1,5-bis(3,4-dichlorophenyl)-3-formazancarbonitrile (1.0 gram; 0.0026mole) and sodium methoxide (0.14 gram; 0.0026 mole) were reacted in 300ml of methanol. The reaction mixture was stirred overnight at roomtemperature, then filtered and the methanol evaporated off to obtain thedesired product, m.p. 312°-314° C.

Quaternary Ammonium Salt Prepared Using Quaternary Ammonium Salt ofCyanoacetamide

The trimethyloctadecylammonium salt of1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile was preparedas follows:

Sodium nitrite (9.10 grams; 0.132 mole) in 20 ml of water was slowlyadded to a solution of 4-(trifluoromethyl)aniline (19.32 grams; 0.12mole) in 200 ml of 2N HCl at 0°-5° C. 2-Cyanoacetamide (5.04 grams; 0.06mole) in 80 ml of water was then added dropwise. The reaction mixturewas stirred 20 minutes, filtered, and added dropwise totrimethyloctadecylammonium bromide (35.0 grams; 0.07 mole) in a mixtureof 250 ml of 2N sodium hydroxide and 500 ml of methanol, at roomtemperature. A slight rise in temperature occurred. The reaction mixturewas stirred overnight. About 1.5 liters of water were added and thereaction mixture was stirred. Solvent was then removed, yieldingapproximately 31 grams of an orange solid. It was mixed with about 100ml of ethyl acetate and filtered. The product melted at 86°-88° C.

Formazan/Levamisole Salt

0.1N Sodium hydroxide (13 ml) was added to levamisole hydrochloride(0.33 gram; 0.0014 mole) in 10 ml of water. The free levamisole wasextracted into 20 ml of methylene chloride, washed once with water, anddried over magnesium sulfate. It was then added to a solution of1,5-bis(4-trifluoromethyl)phenyl)-3-formazancarbonitrile (0.5 gram;0.0013 mole) in 75 ml of methylene chloride. The reaction mixture wasallowed to stir for an hour and the methylene chloride was thenevaporated off, leaving a gummy solid. It was analyzed by NMR, whichconfirmed the formation of the levamisole salt of1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile.

Confirmation was based on the following.

Conversion of 1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrileto its tetramethylammonium salt results in two significant NMR changeswhich are also observed with the levamisole salt.

    ______________________________________                                                aromatic protons                                                                            proton at 1(5)-position                                 ______________________________________                                        parent    7.8-8.1 ppm (multiplet)                                                                       12-13 ppm                                           tetramethyl-                                                                            7.65 ppm (sharp peak)                                               (ionized, proton                                                              ammonium                  shifted upfield)                                    salt                                                                          levamisole salt                                                                         7.65 ppm (sharp peak)                                               (ionized, proton                                                                                        shifted upfield)                                    ______________________________________                                    

Similarly, conversion of levamisole to its hydrochloride salt results intwo significant NMR changes which are also observed with the formazansalt.

    ______________________________________                                                                      protons at                                              aromatic                                                                              proton at 6-  2, 3, and 5-                                            protons position      positions                                       ______________________________________                                        parent    7.35 ppm   5.3 ppm (triplet)                                                                          2.8-3.7 ppm                                                                   (multiplet)                                 HCl salt   7.4 ppm   5.7 ppm (triplet)                                                                          3.5-4.3 ppm                                                                   (multiplet)                                 formazan salt                                                                           7.65 ppm  5.45 ppm (triplet)                                                                          3.1-3.9 ppm                                                                   (multiplet)                                 ______________________________________                                    

Representative compounds to be employed in the present invention,prepared by the foregoing synthetic procedures, include those in thefollowing table.

    __________________________________________________________________________    Formazans                                                                      ##STR12##                                                                    # Substituent on 1-φ                                                                  Substituent on 5-φ                                                                  Salt:      Chemical Name           m.p.                 __________________________________________________________________________                                                             (C.)                  1                                                                              4-Br      4-Br      --         1,5-bis(4-bromophenyl)-3-formazancarbonit                                     rile                    250-253°       2                                                                              3,4-diCl  3,4-diCl  --         1,5-bis(3,4-dichlorophenyl)-3-formazan-                                                               253-255°                                       carbonitrile                                  3                                                                              3,4-diCl  3,4-diCl  Na         1,5-bis(3,4-dichlorophenyl)-3-formazan-                                                               312-314°                                       carbonitrile sodium salt                      4                                                                              2-CF.sub.3                                                                              2-CF.sub.3                                                                              --         1,5-bis(2-(trifluoromethyl)phenyl)-3-form                                     azan-                   159-161°                                       carbonitrile                                  5                                                                              3-CF.sub.3                                                                              3-CF.sub.3                                                                              --         1,5-bis(3-(trifluoromethyl)phenyl)-3-form                                     azan-                   198-200°                                       carbonitrile                                  6                                                                              4-CF.sub.3                                                                              4-CF.sub.3                                                                              --         1,5-bis(4-(trifluoromethyl)phenyl)-3-form                                     azan-                   234-236°                                       carbonitrile                                  7                                                                              4-CF.sub.3                                                                              4-CF.sub.3                                                                              Na         1,5-bis(4-(trifluoromethyl)phenyl)-3-form                                     azan-                   245°                                           carbonitrile sodium salt                                                                              (dec.)                8                                                                              4-CF.sub.3                                                                              4-CF.sub.3                                                                              tetramethyl-                                                                             1,5-bis(4-(trifluoromethyl)phenyl)-3-form                                     azan-                   171-173°                            ammonium   carbonitrile tetramethylammonium salt         9                                                                              4-CF.sub.3                                                                              4-CF.sub.3                                                                              tetraethyl-                                                                              1,5-bis(4-(trifluoromethyl)phenyl)-3-form                                     azan-                   188-191°                            ammonium   carbonitrile tetraethylammonium salt         10                                                                              4-CF.sub.3                                                                              4-CF.sub.3                                                                              tetra-n-propyl-                                                                          1,5-bis(4-(trifluoromethyl)phenyl)-3-form                                     azan-                   223-225°                            ammonium   carbonitrile tetra-n-propylammonium salt     11                                                                              4-CF.sub.3                                                                              4-CF.sub.3                                                                              tetra-n-butyl-                                                                           1,5-bis(4-(trifluoromethyl)phenyl)-3-form                                     azan-                   119-121°                            ammonium   carbonitrile tetra-n-butylammonium salt      12                                                                              4-CF.sub.3                                                                              4-CF.sub.3                                                                              tetra-n-pentyl-                                                                          1,5-bis(4-(trifluoromethyl)phenyl)-3-form                                     azan-                   77-79°                              ammonium   carbonitrile tetra-n-pentylammonium salt     13                                                                              4-CF.sub.3                                                                              4-CF.sub.3                                                                              trimethyloctadecyl-                                                                      1,5-bis(4-(trifluoromethyl)phenyl)-3-form                                     azan-                   86-88°                              ammonium   carbonitrile trimethyloctadecylammonium                                       salt                                         14                                                                              4-OCF.sub.3                                                                             4-OCF.sub.3                                                                             --         1,5-bis(4-(trifluoromethoxy)phenyl)-3-for                                     ma-                     213-214°                                       zancarbonitrile                              15                                                                              4-OCF.sub.3                                                                             4-OCF.sub.3                                                                             Na         1,5-bis(4-(trifluoromethoxy)phenyl)-3-for                                     ma-                     228-230°                                       zancarbonitrile sodium salt                  16                                                                              4-SCF.sub.3                                                                             4-SCF.sub.3                                                                             --         1,5-bis(4-(trifluoromethylthio)phenyl)-3-                                     forma-                  216-219°                                       zancarbonitrile                              17                                                                              4-CF.sub.3                                                                              4-OSO.sub.2 CF.sub.3 1-(4-(trifluoromethyl)phenyl)-5-(4-(trifl                                     uoro-                   182-184°                                       methylsulfonyloxy)phenyl)-3-formazan                                          carbonitrile                                 18                                                                              4-OSO.sub.2 CF.sub.3                                                                    4-OSO.sub.2 CF.sub.3                                                                    --         1,5-bis(4-trifluoromethylsulfonyloxy)phen                                     yl)-3-                  189-191°                                       formazancarbonitrile                         19                                                                              4-OCF.sub.2 CF.sub.2 H                                                                  4-OCF.sub.2 CF.sub.2 H                                                                  --         1,5-(bis(4-(1,1,2,2-tetrafluoroethoxy)phe                                     nyl)-3-                 212-214°                                       formazancarbonitrile                         20                                                                              2-Cl      2-Cl      --         1,5-bis(2-chlorophenyl)-3-formazan                                                                    --                                                    carbonitrile                                 21                                                                              2-F       2-F       --         1,5-bis(2-fluorophenyl)-3-formazan                                                                    --                                                    carbonitrile                                 22                                                                              2-Cl-5-CF.sub.3                                                                         2-Cl-5-CF.sub.3                                                                         --         1,5-bis(2-chloro-5-(trifluoromethyl)pheny                                     l)-3-                   129°                                           formazancarbonitrile    (dec.)               23                                                                              2-F-5-CF.sub.3                                                                          2-F-5-CF.sub.3                                                                          --         1,5-bis(2-fluoro-5-(trifluoromethyl)pheny                                     l)-3-                   --                                                    formazancarbonitrile                         24                                                                              2,3,4,5,6-penta Cl                                                                      2,3,4,5,6-penta Cl                                                                      --         1,5-bis(2,3,4,5,6-pentachlorophenyl)-3-                                                               --                                                    formazancarbonitrile                         25                                                                              2,3,4-tri F                                                                             2,3,4-tri F                                                                             --         1,5-bis(2,3,4-trifluorophenyl)-3-                                                                     138-140°                                       formazancarbonitrile                         26                                                                              4-F       4-F       --         1,5-bis(4-fluorophenyl)-3-formazancarboni                                     trile                   234-236°      27                                                                              4-Cl      4-CF.sub.3                                                                              --         1-(4-chlorophenyl)-5-(4-(trifluoromethyl)                                     phenyl)-                242-244°                                       3-formazancarbonitrile                       28                                                                              4-Cl      4-Cl      --         1,5-bis(4-chlorophenyl)-3-formazancarboni                                     trile                   255°                                                                   (dec)                29                                                                              4-SCH.sub.2 CF.sub.3                                                                    4-SCH.sub.2 CF.sub.3                                                                    --         1,5-bis(4-(2,2,2-trifluoroethylthio)pheny                                     l)-3-                   --                                                    formazancarbonitrile                         __________________________________________________________________________

Certain of the compounds are preferred over others. Symmetricalformazans are preferred because of their ease of preparation. The singlemost preferred compound is1,5-(bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile and itssalts. Among salts, the quaternary ammonium salts, those of the formula##STR13## are preferred because they are soluble in lipids such asvegetable oils, and insoluble in water. These salts exhibit increasedbioavailability in animals.

The present methods can be utilized for protection against a wide rangeof parasitic organisms. Protection is achieved in animals with existingparasitic infections, by eliminating the existing parasites, and/or inanimals susceptible to attack by parasitic organisms, by preventingparasitic attack. Thus, "protection" includes both treatment andprevention.

Representative blood-ingesting parasitic organisms include thefollowing:

Platyhelminthes:

Trematoda such as:

Clonorchis

Echinostoma

Fasciola hepatica (liver fluke)

Fascioloides magna

Fasciolopsis

Metagonimus

Paragonimus

Schistosoma spp.

Nemathelminthes:

Ancylostomum

Angiostrongylus

Anisakis

Ascaris

Brugia

Bunostomum

Cooperia

Dictyocaulus (lungworm)

Dipetalonema

Dirofilaria (heartworm)

Dracunculus

Elaeophora

Gaigeria

Globocephalus urosubulatus

Haemonchus

Metastrongylus (lungworm)

Muellerius (lungworm)

Necator americanus

Onchocerca

Ostertagia

Protostrongylus (lungworm)

Setaria

Stephanofilaria

Syngamus

Toxascaris

Toxocara

Trichinella

Uncinaria stenocephala

Wucheria bancrofti

Arthropoda

Crustacea

Argulus

Caligus

Arachnida

Amblyomma americanum (Lone-star tick)

Amblyomma maculatum (Gulf Coast tick)

Argas persicus (fowl tick)

Boophilus microplus (cattle tick)

Demodex bovis (cattle follicle mite)

Demodex canis (dog follicle mite)

Dermacentor andersoni (Rocky Mountain spotted fever tick)

Dermacentor variabilis (American dog tick)

Dermanyssus gallinae (chicken mite)

Ixodes ricinus (common sheep tick)

Knemidokoptes gallinae (deplumming mite)

Knemidokoptes mutans (scaly-leg mite)

Otobius megnini (ear tick)

Psoroptes equi (scab mite)

Psoroptes ovis (scab mite)

Rhipicephalus sanguineus (brown dog tick)

Sarcoptes scabiei (mange mite)

Insecta:

    ______________________________________                                                Aedes                                                                         Anopheles                                                                     Culex         (mosquitoes)                                                    Culiseta                                                              ______________________________________                                    

Bovicola bovis (cattle biting louse)

Callitroga hominivorax (blowfly)

Chrysops spp. (deer fly)

Cimex lectularius (bed bug)

Ctenocephalis canis (dog flea)

Ctenocephalis felis (cat flea)

Culicoides spp. (midges, sandflies, punkies, or no-see-ums)

Damalinia ovis (sheep biting louse)

Dermatobia spp. (warble fly)

Dermatophilus spp. (fleas)

Gasterophilus haemorrhoidalis (nose bot fly)

Gasterophilus intestinalis (common horse bot fly)

Gasterophilus nasalis (chin fly)

Glossina spp. (tsetse fly)

Haematobia irritans (horn fly, buffalo fly)

Haematopinus asini (horse sucking louse)

Haematopinus eurysternus (short nose cattle louse)

Haematopinus ovillus (body louse)

Haematopinus suis (hog louse)

Hydrotaea irritans (head fly)

Hypoderma bovis (bomb fly)

Hypoderma lineatum (heel fly)

Linognathus ovillus (body louse)

Linognathus pedalis (foot louse)

Linognathus vituli (long nosed cattle louse)

Lucilia spp. (maggot fly)

Melophagus ovinus (sheep ked)

Oestrus ovis (nose bot fly)

Phormia regina (blowfly)

Psorophora

Reduvirus spp. (assassin bug)

Simulium spp. (black fly)

Solenopotes capillatus (little blue cattle louse)

Stomoxys calcitrans (stable fly)

Tabanus spp. (horse fly)

Representative non-blood-sucking intestinal parasites include thefollowing:

Cooperia spp.

Oesophagostomum spp. (nodular worm)

Trichuris

Chabertia (large bowel worm)

Trichostrongylus spp.

Monezia expansa (tapeworm)

Nematodirus spathiger

Parasitic organisms which live in feces are typically the egg and larvalstages of insects such as

Musca domestica (housefly)

Musca autumnalis (face fly)

Haematobia spp. (horn fly, buffalo fly, and others).

The amount of present active agent which is to be employed is notcritical and will vary with the identity of the host, the identity ofthe parasite, the route of administration, whether single or multipledosing is employed, and other factors known to those skilled in the art.For single dosing, a dose of from 1.0 to 50 mg/kg, and preferably from 5to 40 mg/kg, will generally be effective. In situations where the hostis subject to continuing parasitic pressure, it is generally preferredthat the compound of the present invention be administered more thanonce, such as intermittently over the period of time that the host issubject to parasitic attack. This may be for a brief period of days orseveral weeks, for a season, or up to a lifetime. Sustained releaseformulations, which provide delivery over a period of time, aretherefore often preferred. When repeated dosing is employed, thecompounds can be used at lower rates, such as from 0.1 to 10 mg/kg perday. All doses described above are based on the parent compound ofFormula I; when a salt is employed, a correspondingly higher amountshould be used to provide the indicated amount of the parent compound.As an exception, however, when the salt is with a parasiticidally activecompound such as levamisole, the amount of the parent compound ofFormula I can be reduced.

For the control of blood-ingesting parasites, the present compounds mustbe delivered in a manner to enter and spread through the circulatorysystem of the host. However, it has been found that this can be achievedby any of numerous routes of administration, for example, intramuscular,intraruminal, intravenous, oral, subcutaneous, and transdermal. If thecompound is orally or intraruminally delivered, it may be desirable toprotect the compound during its passage through the rumen. Techniquesfor achieving this are well known.

For the control of non-blood-ingesting intestinal parasites and theinhibition of parasitic organisms in feces, the present compounds mustbe present in the intestinal tract; most conveniently, the compounds aredelivered orally or intraruminally.

For some modes of delivery, such as in gelatin capsules, the presentcompounds can be employed neat. However, for most delivery techniques,the compounds are formulated with one or more physiologically acceptablecarriers. Formulation techniques are well known in medical andveterinary practice and can readily be chosen for the present inventionby those skilled in the art. For oral delivery, the compounds can beformulated in solid forms such as tablets including chewable tablets,capsules, and pastes, or in liquid forms such as syrups, aqueoussuspensions, solutions, drenches, and the like. The compounds can alsobe formulated as boluses. With appropriate design and formulation, thebolus will remain in the rumen of ruminants and provide continued payoutof the compound of the present invention over a period of time.

The compounds are conveniently administered to livestock animals via afeedstuff, via the drinking water, or via a mineral block. In the caseof feedstuffs, the compound is typically incorporated in a premix whichis subsequently added to other feed components to form the finishedfeed. The compounds can also be formulated as part of the drinkingwater.

The compounds can also be administered by intraruminal, intramuscular,intravenous, or subcutaneous injection. Typically the compound isformulated in vehicles of lipophilic nature, such as animal or vegetableoils. Parenteral formulations which provide delayed delivery can also beused in delivering the present compounds.

In all of the foregoing formulations, the compounds are mixed withphysiologically acceptable carriers suited for the particular mode ofdelivery. The concentration of the present compound is not critical andwill vary with the particular mode of delivery. Thus the concentrationmay range from 0.1 to 95 percent weight/volume; and in many instancesfrom 1 to 50 percent, weight/volume.

In the control of parasites, combinations are frequently used, tominimize the development of resistance, to increase the spectrum ofparasite control, and to minimize the risk of side effects. Therefore,the present compounds can also be employed in combination with one ormore known anthelmintics (endectocides) or with one or more knownectoparasiticides. Preferred combinations are those with anthelmintics.Representative known parasiticides with which the present compounds canbe combined include the following:

among the anthelmintics:

albendazole

bunamidine

coumaphos

dichlorvos

epsiprantel

febantel

fenbendazole

flubendazole

ivermectin

levamisole

mebendazole

milbemycin

morantel

moxidectin

netobimin

niclosamide

nitroscanate

oxfendazole

oxibendazole

piperazine

praziquantel

pyrantel

ricobendazole

tetramisole

thiabendazole

among the flukicides:

clorsulon

closantel

diamphenethide

nitroxynil

oxyclozanide

rafoxanide

triclabendazole

among the ectoparasiticides:

alphamethrin

amitraz

coumaphos

cycloprothrin

cyfluthrin

cyhalothrin

cypermethrin

cyromazine

deltamethrin

diazinon

diflubenzuron

dioxathion

fenthion

fenvalerate

flucythrinate

flumethrin

ivermectin

methoprene

metriphonate

moxidectin

permethrin

phosmet

pirimiphos

propetamphos

propoxur

rotenone

temephos

tetrachlorvinphos

The present invention is illustrated by the following examples.

The compounds were formulated for evaluation in animals. Most typically,a compound was formulated by merely dissolving it in polyethylene glycol200 (referred to below as a PEG 200 formulation). Other formulationswere utilized for many of the tests; in these other formulations, theparticular compound was in most instances dissolved in eitherN-methyl-2-pyrrolidone or ethyl acetate, and then extended with refinedsesame oil. Commonly, Span 80 (a sorbitan monooleate nonionic surfactantsold by ICI Americas Inc.) was also added. The following formulationswere prepared.

FORMULATIONS A & B

    ______________________________________                                        1,5-bis(4-(trifluoromethyl)phenyl)-3-                                                                  452.4  mg                                            formazancarbonitrile                                                          N-methyl-2-pyrrolidone   2.25   ml                                            Sesame oil, refined      6.75   ml                                            1,5-bis(4-(trifluoromethyl)phenyl)-3-                                                                  351.7  mg                                            formazancarbonitrile                                                          N-methyl-2-pyrrolidone   11.75  ml                                            Sesame oil, refined      4.20   ml                                            Span 80                  1.05   ml                                            ______________________________________                                    

Each of these two formulations contained the compound at 50 mg/ml (5%w/v). They and a vehicle blank were used in conducting Test 5, below.The vehicle blank consisted of the vehicle of Formulation A, that is,N-methyl2-pyrrolidone and refined sesame oil, only.

FORMULATIONS C, D, & E

    ______________________________________                                        1,5-bis(4-(trifluoromethyl)phenyl)-3-                                                                  4204.3  mg                                           formazancarbonitrile                                                          N-methyl-2-pyrrolidone   21.0    ml                                           Sesame oil, refined      21.0    ml                                           1,5-bis(4-(trifluoromethyl)phenyl)-3-                                                                  3996.4  mg                                           formazancarbonitrile                                                          N-methyl-2-pyrrolidone   20.0    ml                                           Sesame oil, refined      16.0    ml                                           Span 80                  4.0     ml                                           1,5-bis(4-(trifluoromethyl)phenyl)-3-                                                                  4204.6  mg                                           formazancarbonitrile                                                          N-methyl-2-pyrrolidone   21.0    ml                                           ______________________________________                                    

The compound concentration in these was 100 mg/ml, 100 mg/ml, and 200mg/ml, respectively (10%, 10%, and 20%, respectively, all w/v). Vehicleblanks were also prepared corresponding to each of the threeformulations. All of these formulations and blanks were utilized inconducting Test 14 below.

FORMULATION F

    ______________________________________                                        1,5-bis(4-(trifluoromethyl)phenyl)-3-                                                                  4500.0  mg                                           formazancarbonitrile                                                          N-methyl-2-pyrrolidone   22.5    ml                                           Sesame oil, refined      18.0    ml                                           Span 80                  4.5     ml                                           ______________________________________                                    

The compound concentration was 100 mg/ml (10% w/v). A vehicle blank wasalso prepared. This formulation and vehicle blank were employed inconducting Tests 9 and 15, below.

FORMULATION G

    ______________________________________                                        Tetra-n-butylammonium salt of 1,5-bis(4-                                                                7994.4  mg                                          (trifluoromethyl)phenyl)-3-formazancarbonitrile                               N-methyl-2-pyrrolidone    40.0    ml                                          Sesame oil, refined       32.0    ml                                          Span 80                   8.0     ml                                          ______________________________________                                    

This formulation contained 100 mg of the indicated salt/ml offormulation (10% w/v). It and a vehicle blank were used to conduct Tests10 and 16, below.

FORMULATION H

    ______________________________________                                        1,5-bis(4-(trifluoromethyl)phenyl)-3-                                                                  8045.5  mg                                           formazancarbonitrile                                                          N-methyl-2-pyrrolidone   40.0    ml                                           Sesame oil, refined      32.0    ml                                           Span 80                  8.0     ml                                           ______________________________________                                    

This formulation provided 100 mg of compound/ml of formulation (10%w/v). It and a vehicle blank were employed in conducting Test 12, below.

FORMULATIONS I, J, & K

Salts of 1,5-bis(4-trifluoromethyl)phenyl)-3-formazancarbonitrile wereformulated as follows:

    ______________________________________                                        Tetramethylammonium salt                                                                              4511.2  mg                                            Ethyl acetate           22.5    ml                                            Sesame oil, refined     31.5    ml                                            Span 80                 4.5     ml                                            Tetra-n-propylammonium salt                                                                           4996.4  mg                                            Ethyl acetate           50.0    ml                                            Sesame oil, refined     32.5    ml                                            Span 80                 5.0     ml                                            Trimethyloctadecylammonium salt                                                                       6004.1  mg                                            Ethyl acetate           30.0    ml                                            Sesame oil, refined     39.0    ml                                            Span 80                 6.0     ml                                            ______________________________________                                    

These three formulations contained the respective salt at aconcentration of 76.9 mg/ml (7.69% w/v), 57.14 mg/ml (5.714% w/v), and80 mg/ml (8% w/v), respectively. Additional quantities were preparedwith the same composition. All formulations and the correspondingvehicle blank were employed in conducting Tests 6, 8, and 17, below.

FORMULATIONS L, M, & N

Three additional salts of1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile wereformulated for evaluation, as below:

    ______________________________________                                        Tetra-n-butylammonium salt                                                                            8200.0  mg                                            Ethyl acetate           82.0    ml                                            Sesame oil, refined     53.3    ml                                            Span 80                 8.2     ml                                            Tetraethylammonium salt 6700.0  mg                                            Ethyl acetate           95.75   ml                                            Sesame oil, refined     43.55   ml                                            Span 80                 6.70    ml                                            Tetra-n-pentylammonium salt                                                                           8900.0  mg                                            Ethyl acetate           89.0    ml                                            Sesame oil, refined     57.85   ml                                            Span 80                 8.9     ml                                            ______________________________________                                    

These formulations contained 57.14 mg/ml (5.714% w/v); 45.89 mg/ml(4.589% w/v); and 57.14 mg/ml (5.714% w/v) of the respective salt. Theformulations, along with a vehicle blank, were employed in conductingTests 7 and 22, below.

FORMULATION O

    ______________________________________                                        1,5-bis(4-(trifluoromethyl)phenyl)-3-                                                                 30,000.00                                                                              mg                                           formazancarbonitrile trimethylocta-                                           decylammonium salt                                                            Ethyl acetate           150.0    ml                                           Sesame oil, refined     195.0    ml                                           Span 80                 30.0     ml                                           ______________________________________                                    

Portions of this formulation, containing 80 mg/ml of the activeingredient (8% w/v), and the vehicle control, were employed inconducting Tests 26 and 27, below. The remaining portions, along withFormulation P, were used in conducting Test 23.

FORMULATION P

    ______________________________________                                        1,5-bis(4-(trifluoromethyl)phenyl)-3-                                                                  6000.0  mg                                           formazancarbonitrile trimethylocta-                                           decylammonium salt                                                            Ethyl acetate            30.0    ml                                           Sesame oil, refined      39.0    ml                                           Span 80                  6.0     ml                                           ______________________________________                                    

This formulation contained 80 mg/ml of the salt (8% w/v). It and avehicle blank were employed in conducting Test 23, below.

FORMULATION Q

    ______________________________________                                        1,5-bis(4-(trifluoromethyl)phenyl)-3-                                                                 70,000.00                                                                              mg                                           formazancarbonitrile trimethylocta-                                           decylammonium salt                                                            Ethyl acetate           350.0    ml                                           Sesame oil, refined     455.0    ml                                           Span 80                 70.0     ml                                           ______________________________________                                    

This formulation contained 80 mg/ml (8% w/v); it and a vehicle blankwere used in Test 29.

FORMULATION R

    ______________________________________                                        1,5-bis(4-(trifluoromethyl)phenyl)-3-                                                                 50,000.00                                                                              mg                                           formazancarbonitrile trimethylocta-                                           decylammonium salt                                                            Ethyl acetate           250.0    ml                                           Sesame oil, refined     325.0    ml                                           Span 80                 50.0     ml                                           ______________________________________                                    

This formulation contained 80 mg/ml (8% w/v); it and a vehicle blankwere employed in Tests 13 and 30.

FORMULATION S

An emusifiable concentrate was prepared according to standard proceduresfrom the following ingredients

    ______________________________________                                        1,5-bis(4-(trifluoromethyl)phenyl)-3-                                                                    8500.0  mg                                         formazancarbonitrile trimethylocta-                                           decylammonium salt                                                            Ethyl acetate              42.5    ml                                         Drakeol 6VR (a light mineral oil sold by                                                                 34.0    ml                                         Pennsylvania Refining Company)                                                Montanide 888 (a mannide oleate adjuvant sold by                                                         8.5     ml                                         Seppic, Paris, France)                                                        ______________________________________                                    

to provide a concentration of 100 mg/ml of the active ingredient (10%w/v). This formulation and a vehicle blank were employed in Test 24.

FORMULATION T

Another emulsifiable concentrate was prepared from the followingingredients

    ______________________________________                                        1,5-bis(4-(trifluoromethyl)phenyl)-3-                                                                 13,000.0 mg                                           formazancarbonitrile trimethylocta-                                           decylammonium salt                                                            Ethyl acetate           65.0     ml                                           Drakeol 6VR             52.0     ml                                           Montanide 888           13.0     ml                                           ______________________________________                                    

to provide a concentration of 100 mg of the active ingredient per ml(10% w/v). This formulation and a vehicle blank were used in Test 25.

FORMULATION U

The following formulation was prepared

    ______________________________________                                        1,5-bis(4-(trifluoromethyl)phenyl)-3-                                                                  6000.0  mg                                           formazancarbonitrile trimethylocta-                                           decylammonium salt                                                            Ethyl acetate            30.0    ml                                           Sesame oil, refined      39.0    ml                                           Span 80                  6.0     ml                                           ______________________________________                                    

to provide 80 mg of active ingredient per ml (8% w/v). The formulationand a vehicle blank were utilized in Test 28.

FORMULATION V

An aqueous suspension was prepared according to standard procedures fromthe following materials:

    ______________________________________                                        1,5-bis(4-(trifluoromethyl)phenyl)-3-                                                                  4.00   g                                             formazancarbonitrile trimethylocta-                                           decylammonium salt                                                            Propylene glycol         5.00   g                                             Tergitol + TMN-6 (an ethoxylated                                                                       2.00   g                                             trimethylnonanol nonionic surfactant                                          sold by Union Carbide Corp.)                                                  2% Xanthan gum solution  5.00   g                                             Polyfon H (a sodium lignosulfonate,                                                                    0.25   g                                             sold by Westvaco Corp.)                                                       Water, purified          33.65  g                                             Antifoam A (a dimethylpolysiloxane,                                                                    0.10   g                                             sold by Dow Corning)     50.00  g                                             ______________________________________                                    

This formulation provided 80 mg of active ingredient per ml (8% w/v).

FORMULATION W

Gelatin capsules were prepared, for evaluation in dogs. Two salts of1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile were used, thetetramethylammonium salt and the trimethyloctadecylammonium salt. Eachof the salts was air milled in a Troust Laboratory Air Mill to a medianparticle size of approximately 10 to 20 microns, and then filled into #0gelatin capsules, in the amount of 150 mg of the tetramethylammoniumsalt per capsule, and 225 mg of the trimethyloctadecylammonium salt percapsule. Placebos were prepared with the same size of gelatin capsules,each filled with 225 mg of sucrose.

TESTS AGAINST Phormia regina (blow fly) and Stomoxys calcitrans (stablefly)

Various of the compounds to be employed in the present invention wereevaluated in preliminary tests for the control of the larval phase ofthe adult stage of Stomoxys calcitrans (stable fly). This preliminarytest employed a stock solution of the respective compound. This sametest was also conducted as an adjunct to in vivo tests reported below.In this instance, the test employed serum (or in some cases, wholeblood) from treated animals. The preliminary test was conducted againstonly Stomoxys calcitrans (stable fly); testing of serum or whole bloodwas against both Stomoxys calcitrans as well as Phormia regina (blowfly). The test precedures were as follows.

The compound to be evaluated was dissolved in 1 part acetone/1 partethanol to provide a stock solution of the compound at a concentrationof 5,000 ppm; this solution was shaken for 15 minutes on a sonicator.Portions of the stock solution were placed in 15 ml test tubes, andportions of bovine serum were added to provide the desired dilution ofthe test compound. Alternately, a sample of serum or blood was used andplaced in the test tubes. A dental wick was placed in each test tube andthe serum allowed to saturate the wick.

For the blow fly test, approximately 20 blow fly larvae were placed ontothe top center of the saturated dental wick, and the test tube wasplugged with cotton and incubated at 27° C. and 70% humidity for 24 and48 hours. Larval mortality counts were then made, and adjusted for anymortality in the vehicle control, to determine percent efficacy againstblow fly.

For the adult stable fly test, the saturated wick was placed on a filterpaper in a petri dish, and approximately 10 chilled live, hungry stablefiles were placed on the center of the dish bottom. The dish was coveredand allowed to incubate at 27° C. and 60% relative humidity for 48hours. Mortality readings were made at each of 24 and 48 hours, andadjusted for any mortality in the vehicle control, to determine percentefficacy against adult stable fly.

The results of the stable fly tests which were conducted using stocksolution and untreated bovine serum are set forth in the followingtable. Tests using bovine serum or blood from treated animals arereported below.

    ______________________________________                                                                 Percent                                                                       Efficacy                                                                      against                                                                Concen-                                                                              Adult Stable fly                                                         tration  24      48                                       Test Compound       (ppm)    hours   hours                                    ______________________________________                                        1,5-bis(4-bromophenyl)-3-                                                                         100      60      100                                      formazancarbonitrile                                                                              50       90      100                                                          25       NT      100                                                          10       50       90                                                          25       40      NT                                                           10       40      100                                                          5         0       80                                                          2.5       0       40                                                          1.25     30       40                                      1,5-bis(3,4-dichlorophenyl)-3-                                                                    100      100     100                                      formazancarbonitrile                                                                              100      100     100                                                          50       80      100                                                          25       40       70                                                          10       40       60                                                          25       10       90                                                          10       20       50                                                          5        10       10                                                          2.5      10       10                                      1,5-bis(3,4-dichlorophenyl)-3-                                                                    100      100     100                                      formazancarbonitrile sodium salt                                                                  100      100     100                                                          50       90      100                                                          25       80      100                                                          10       80      100                                                          25       90      100                                                          10       90      100                                                          5        80      100                                                          2.5      80      100                                                          10       60      100                                                          5        30       90                                                          2        40      100                                                          1        10       50                                                          0.5       0       20                                      1,5-bis(4-(trifluoromethyl)phenyl)-3-                                                             100      100     100                                      formazancarbonitrile                                                                              50       100     100                                                          25       80      100                                                          10       70      100                                                          25       100     100                                                          10       60      100                                                          5        40       90                                                          2.5       0       60                                                          10       100     100                                                          5        90      100                                                          2        80      100                                                          1        60      100                                                          0.5      20       70                                      1,5-bis(4-(trifluoromethyl)phenyl)-3-                                                             5        60      100                                      formazancarbonitrile                                                                              2        30      100                                      tetramethylammonium salt                                                                          1        20      100                                                          0.5       0       40                                      1,5-bis(4-(trifluoromethyl)phenyl)-3-                                                             100      100     100                                      formazancarbonitrile                                                                              50       100     100                                      tetraethylammonium salt                                                                           25       80      100                                                          10       50       90                                                          5        50       90                                                          5        20      100                                                          2        10       80                                                          1        20       20                                                          0.5      10       10                                      1,5-bis(4-(trifluoromethyl)phenyl)-3-                                                             100      100     100                                      formazancarbonitrile tetra-n-                                                                     50       100     100                                      propylammonium salt 25       80      100                                                          10       80      100                                                          10       60      100                                                          5        70      100                                                          2        40       90                                                          1        40       70                                                          0.5      20       30                                      1,5-bis(4-(trifluoromethyl)phenyl)-3-                                                             100      90      100                                      formazancarbonitrile tetra-n-                                                                     50       90      100                                      butylammonium salt  25       80      100                                                          10       40      100                                                          10       20      100                                                          5        40      100                                                          2        60       90                                                          1         0       70                                                          0.5      20       50                                      1,5-bis(4-(trifluoromethyl)phenyl)-3-                                                             100      100     100                                      formazancarbonitrile tetra-n-                                                                     50       70      100                                      pentylammonium salt 25       60      100                                                          10       40      100                                                          10       40      100                                                          5        40      100                                                          2        40       80                                                          1        40       70                                                          0.5      20       60                                      1,5-bis(4-(trifluoromethyl)phenyl)-3-                                                             100      100     100                                      formazancarbonitrile                                                                              50       100     100                                      trimethyloctadecylammonium salt                                                                   25       80      100                                                          10       40      100                                                          10       90      100                                                          5        80      100                                                          2        80       90                                                          1        50       90                                                          0.5      40       50                                                          25       100     NT                                                           10       80      NT                                                           5        40      NT                                                           2.5      10      NT                                                           1         0      NT                                                           25       100     NT                                                           10       100     NT                                                           5        50      NT                                                           2.5      10      NT                                                           1         0      NT                                       1,5-bis(4-(trifluoromethoxy)phenyl)-3-                                                            100      100     100                                      formazancarbonitrile                                                                              100      100     100                                                          50       90      100                                                          25       100     100                                                          10       70      100                                                          25       100     100                                                          10       80      100                                                          5        60       90                                                          2.5      20       60                                                          10       70      100                                                          5        20      100                                                          2        20       70                                                          1         0       40                                                          0.5      20       30                                      1,5-bis(4-(trifluoromethoxy)phenyl)-3-                                                            100      100     100                                      formazancarbonitrile sodium salt                                                                  25       90      100                                                          10       70      100                                                          5        20       90                                                          2.5      20       80                                                          10       70      100                                                          5        50      100                                                          2        30       70                                                          1        10       10                                                          0.5      20       20                                      1,5-bis(4-(trifluoromethylthio)phenyl)-                                                           100      100     100                                      3-formazancarbonitrile                                                                            50       100     100                                                          25       100     100                                                          10       80      100                                                          5        70      100                                                          10       80      100                                                          5        60      100                                                          2.5      40      100                                                          1.25     30       70                                                          10       80      100                                                          5        70      100                                                          2        40       90                                                          1        30       70                                                          0.5      30       40                                      1-(4-(trifluoromethyl)phenyl)-5-(4-                                                               100      100     100                                      (trifluoromethylsulfonyloxy)phenyl)-                                                              50       100     100                                      3-formazancarbonitrile                                                                            25       100     100                                                          10       100     100                                                          10       90      100                                                          5        50      100                                                          2.5      50       80                                                          1.25      0       40                                                          0.625     0       20                                      1,5-bis(4-          100      100     100                                      trifluoromethylsulfonyloxy)phenyl-3-                                                              50       100     100                                      formazancarbonitrile                                                                              25       100     100                                                          10       90      100                                                          5        70      100                                                          2.5      20       20                                                          1.25     10       20                                                          0.625    10       10                                                          50       100     100                                                          20       60      100                                                          10       20       90                                                          5         0       10                                                          10       70      100                                                          5        10       70                                                          2.5      10       30                                                          1.25      0       20                                                          0.625     0       10                                      1,5-bis(4-(1,1,2,2- 100      80      100                                      tetrafluoroethoxy)phenyl)-3-                                                                      100      90      100                                      formazancarbonitrile                                                                              50       70      100                                                          25       50      100                                                          10       50      100                                      ______________________________________                                         NT = Not Tested                                                          

TEST AGAINST HAEMONCHUS CONTORTUS IN SHEEP (Test 1-10 and Tables 1-10)

Representative compounds to be employed in the present invention wereevaluated in wormy sheep; these sheep were naturally infected withHaemonchus contortus and oftentimes were additionally infected withother species, mostly Trichostrongylus colubriformis. The evaluationswere carried out as follows. The respective compound was formulated, inmany tests by simply dissolving it in polyethylene glycol 200 ("PEG 200Formulation"). Each formulation was administered to the sheep, generallyas a single intraruminal injection. Typically there were two sheep ineach treatment group and one sheep in the vehicle control group. Fecalmaterial was collected daily both pre and post treatment, and the numberof eggs/gram of feces was determined. For those animals with >75%reduction in eggs/gram of feces, the total worm passage was determinedand the animals were necropsied and counts made of internal worms notpassed.

In addition, blood samples were taken from the sheep prior toadministration of the test compound, and post treatment at 30 minutes, 5hours, 24 hours, and daily up to 7 days after treatment. These sampleswere evaluated in vitro for control of Phormia regina and Stomoxyscalcitrans, employing the methods described above.

Results of these evaluations are set forth below. Deviations from thegeneral procedures are noted. Throughout the tables, "VC" means thevehicle control. No adverse reactions by the sheep were described in anyof the trials.

                                      TABLE 1A                                    __________________________________________________________________________    Test 1: Evaluation of 1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarboni    trile,                                                                        at 10 mg/kg Bodyweight (PEG 200 Formulation)                                  Activity Against Haemonchus contortus ("H") and Trichostrongylus              colubriformis ("T")                                                           __________________________________________________________________________           Worm Eggs Per Gram of Feces (EPG)                                                     Days Following Treatment                                              Pre*    1       2       3       4      5-7                             Treatment                                                                            H   T   H   T   H   T   H   T   H   T  H   T                           __________________________________________________________________________    Treated                                                                              867 133 200 200  0   0   0   0   0  0   0   0                          Treated                                                                              933 700 600 400 300 900  0  400  0  0   0  466.7                       VC     533  0  800  0  500  0  600  0  900 0  733  0                          __________________________________________________________________________                        % EPG    Total Number Worm                                                                              Percent                                             Reduction                                                                              Passed   Counts.sup.1                                                                          Reduction                                    Treatment                                                                            H   T    H    T   H   T   H   T                           __________________________________________________________________________                 Treated                                                                              100 100  117**                                                                              ND  0     0 100 100                                      Treated                                                                              100   33.4                                                                              11**                                                                              ND  0   393 100 ND                                       VC      0  --   ND   ND  ND  ND                                  __________________________________________________________________________     *Average of 3 days sampling                                                   **Very small immature 75% F                                                   .sup.1 At necropsy 7 days following treatment                                 ND = not done                                                            

                                      TABLE 1B                                    __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 24 hr in vitro Exposure                                             Day       30  5     Day   Day  Day Day Day Day Day                            0         Min Hr    1     2    3   4   5   6   7                              Treatment                                                                           L A L A L  A  L  A  L  A L A L A L A L A L A                            __________________________________________________________________________    Treated                                                                             0 0 0 10                                                                              100                                                                              100                                                                              100                                                                              100                                                                               75                                                                              20                                                                              0 0 0  0                                                                              0 10                                                                              0 10   0                                                                        0                                Treated                                                                             0 0 0 10                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              60                                                                              0 0 0  0                                                                              0  0                                                                              0  0   0                                                                        0                                VC    0 0 0  0                                                                               0  0  0  0  0  0                                                                              0 0 0 10                                                                              0 10                                                                              0  0   0                                                                        0                                __________________________________________________________________________

                                      TABLE 1C                                    __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 48 hr in vitro Exposure                                             Day       30  5     Day   Day   Day  Day Day Day Day                          0         Min Hr    1     2     3    4   5   6   7                            Treatment                                                                           L A L A L  A  L  A  L  A  L A  L A L A L A L A                          __________________________________________________________________________    Treated                                                                             0 0 0 0 100                                                                              100                                                                              100                                                                              100                                                                               90                                                                               70                                                                              0 100                                                                              0 20                                                                              0 10                                                                              0 0    0                                                                        0                              Treated                                                                             0 0 0 0 100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              0  30                                                                              0  0                                                                              0  0                                                                              0 0    0                                                                        0                              VC    0 0 0 0  0  0  0  0  0  0 0  0 0  0                                                                              0  0                                                                              0 0    0                                                                        0                              __________________________________________________________________________

                                      TABLE 2A                                    __________________________________________________________________________    Test 2: Evaluation of 1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarboni    trile,                                                                        at 5 mg/kg Bodyweight (PEG 200 Formulation)                                   Activity Against Haemonchus contortus ("H") and Trichostrongylus              colubriformis ("T")                                                                  Worm Eggs Per Gram of Feces (EPG)                                                   Days Following Treatment                                                                        % EPG   Total Number Worm                                                                             Percent of                    Pre*  1     2     5-7   Reduction                                                                             Passed  Counts.sup.1                                                                          Worms                  Treatment                                                                            H  T  H  T  H  T  H  T  H   Others                                                                            H   Others                                                                            H   Others                                                                            H   Others             __________________________________________________________________________    Treated                                                                              7833                                                                             433                                                                              5900                                                                             200                                                                                0                                                                              100                                                                                0                                                                               0 100 100 0   ND   0   0  100 100                Treated                                                                              5533                                                                             433                                                                              2600                                                                             300                                                                               100                                                                             200                                                                                0                                                                              250                                                                              100   42.3                                                                             17**                                                                             ND   0   29 100   87.8             VC     1767                                                                             300                                                                              2800                                                                             100                                                                              1900                                                                             100                                                                              2750                                                                             300                                                                               0   0  0   ND  840 238 --  --                 __________________________________________________________________________     *Average of 3 days sampling                                                   **Pieces of worms                                                             .sup.1 At necropsy 7 days following treatment                                 ND = not done                                                                 Others = identified as Trichostrongylus colubriformis and Ostertagia spp.

                                      TABLE 2B                                    __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 24 hr in vitro Exposure                                             Day       30  5     Day   Day  Day Day Day                                    0         Min Hr    1     2    3   4   5                                      Treatment                                                                           L A L A L  A  L  A  L  A L A L A L A                                    __________________________________________________________________________    Treated                                                                             0 10                                                                              0 0 100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              60                                                                              25                                                                               0                                                                              0  0                                                                              0 20                                   Treated                                                                             0  0                                                                              0 0 100                                                                               90                                                                              100                                                                              100                                                                               0  0                                                                               0                                                                               0                                                                              0 10                                                                              0  0                                   VC    0 10                                                                              0 0  0  0  0  0  0  0                                                                               0                                                                              20                                                                              0  0                                                                              0 10                                   __________________________________________________________________________

                                      TABLE 2C                                    __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 48 hr in vitro Exposure                                             Day       30  5     Day   Day   Day  Day  Day                                 0         Min Hr    1     2     3    4    5                                   Treatment                                                                           L A L A L  A  L  A  L  A  L A  L A  L A                                 __________________________________________________________________________    Treated                                                                             0 20                                                                              10                                                                              70                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              90                                                                              100                                                                              60                                                                              100                                                                              0 100                               Treated                                                                             0  0                                                                               0                                                                              20                                                                              100                                                                              100                                                                              100                                                                              100                                                                               10                                                                              100                                                                               0                                                                               0  0                                                                               20                                                                              0  10                               VC    0  0                                                                               0                                                                               0                                                                               0  0  0  0  0  0  0                                                                               0  0                                                                               0 0  0                                __________________________________________________________________________

                                      TABLE 3A                                    __________________________________________________________________________    Activity Against Haemonchus contortus                                         Test 3: 1,5-bis(4-bromophenyl)-3-formazancarbonitrile (Cmpd 1) at 10          mg/kg and                                                                     1,5-bis(4-(trifluoromethylsulfonyloxy)-3-formazancarbonitrile (Cmpd 18)       at 5 mg/kg,                                                                   Each in PEG 200 Formulation                                                             Worm Eggs Per Gram of Feces (EPG)                                   Dose          Days Following Treatment                                                                     % Worm Egg                                                                            Total Worm                                                                           % Worm                            Treatment                                                                           mg/kg                                                                             Pre*                                                                              1  2  3 4  5-7*                                                                              Reduction                                                                             Counts Reduction                         __________________________________________________________________________    Cmpd 1                                                                              10  733 600                                                                              500  400                                                                              350 52.3    N/D    --                                Cmpd 1                                                                              10  233 100                                                                               0   100                                                                              200 14.2    N/D    --                                Cmpd 18                                                                             5   433 600                                                                              700  400                                                                              500 0       N/D    --                                Cmpd 18                                                                             5   567 500                                                                              500  600                                                                              500 11.8    N/D    --                                VC    0    0   0  0    0  0                                                   __________________________________________________________________________     *Average of 3 days sampling                                                   ND = not done                                                            

                                      TABLE 3B                                    __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L" ) and Stomoxys      calcitrans ("A")                                                              Following 24 hr in vitro Exposure                                             Dose      Day 0                                                                              30 Min                                                                            5 Hr Day 1                                                                             Day 2                                                                             Day 3                                                                             Day 4                                                                             Day 5                                                                              Day 6                            Treatment                                                                           mg/kg                                                                             L A  L A L A  L A L A L A L A L A  L A                              __________________________________________________________________________    Cmpd 1                                                                              10  0 0  0 20                                                                              0 10 0 0 0 0 0 0 0 10                                                                              0 10 0  0                             Cmpd 1                                                                              10  0 20 0 30                                                                              0 10 0 0 0 0 0 0 0 10                                                                              0 0  0  10                            Cmpd 18                                                                             5   0 0  0 10                                                                              0 0  0 0 0 0 0 0 0 20                                                                              0 0  0  10                            Cmpd 18                                                                             5   0 0  0 20                                                                              0 0  0 0 0 0 0 0 0 10                                                                              0 10 0  10                            VC    0   0 0  0  0                                                                              0 0  0 0 0 0 0 0 0  0                                                                              0 0  0   0                            __________________________________________________________________________

                                      TABLE 3C                                    __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 48 hr in vitro Exposure                                             Dose      Day 0                                                                              30 Min                                                                            5 Hr Day 1                                                                             Day 2                                                                             Day 3                                                                             Day 4                                                                             Day 5                                                                              Day 6                            Treatment                                                                           mg/kg                                                                             L A  L A L A  L A L A L A L A L A  L A                              __________________________________________________________________________    Cmpd 1                                                                              10  0 0  0 20                                                                              0 30 0 20                                                                              0  0                                                                              0 30                                                                              0 10                                                                              0 10 0 10                             Cmpd 1                                                                              10  0 20 0 40                                                                              0 10 0 10                                                                              0 30                                                                              0 10                                                                              0 10                                                                              0 0  0  20                            Cmpd 18                                                                             5   0 0  0 30                                                                              0 0  0 20                                                                              0 20                                                                              0 20                                                                              0 30                                                                              0 0  0  10                            Cmpd 18                                                                             5   0 0  0 30                                                                              0 0  0 30                                                                              0 10                                                                              0  0                                                                              0 30                                                                              0 10 0  20                            VC    0   0 0  0  0                                                                              0 0  0 10                                                                              0 20                                                                              0 20                                                                              0 20                                                                              0 0  0   0                            __________________________________________________________________________

                                      TABLE 4A                                    __________________________________________________________________________    Activity Against Haemonchus contortus ("H"), Trichostrongylus                 colubriformis ("T"),                                                          and Ostertagia spp. ("O")                                                     Test 4: Evaluation of                                                         1,5-bis(3,4-dichlorophenyl)-3-formazancarbonitrile (Cmpd 2)                   at 10 mg/kg Bodyweight, and of                                                1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile (Cmpd 6)            at 2.5 mg/kg Bodyweight, Each, PEG 200 Formulation                            __________________________________________________________________________    Worm Eggs Per Gram of Feces (EPG)                                                          Days Following Treatment                                         Pre*         1     2     3     4     5-7*                                     Treatment                                                                           H   T  H  T  H  T  H  T  H  T  H  T                                     __________________________________________________________________________    Cmpd 2                                                                              10500                                                                             500                                                                              7400                                                                             500                                                                              2400                                                                             400                                                                              2300                                                                             300                                                                              1900                                                                             300                                                                              1725                                                                             375                                         3933                                                                              433                                                                              4000                                                                             500                                                                              1600                                                                             300                                                                              1200                                                                             200                                                                              1200                                                                             300                                                                              1200                                                                             183                                   Cmpd 6                                                                              9233                                                                              533                                                                              1400                                                                             600                                                                                0                                                                               0   0                                                                               0   0                                                                               0   0                                                                               0                                          3800                                                                              633                                                                              3000                                                                             400                                                                                0                                                                               0   0                                                                              100                                                                                0                                                                               0   0                                                                               0                                    VC    4033                                                                              300                                                                              2800                                                                             300                                                                              4800                                                                             500                                                                              3400                                                                             400                                                                              3200                                                                             400                                                                              3600                                                                             450                                   __________________________________________________________________________    % Worm                                                                        Egg           Total Number Worm                                               Reduction     Passed                                                                             Counts.sup.1                                                                              % Reduction                                    Treatment                                                                           H   T   H**  H   T   O   H   T   O                                      __________________________________________________________________________    Cmpd 2                                                                              82   30 39   916 27  19   0   73 39                                           72   42 53   556 14  39   13  88 0                                      Cmpd 6                                                                              100 100 20    0   0  105 100 100 0                                            100 100 13    0   0  45  100 100 0                                      VC    11   0   0   637 112 31  --  --  --                                     __________________________________________________________________________     *Average of 3 days sampling                                                   **Mostly pieces of worms                                                      .sup.1 At necropsy 7 days following treatment                            

                                      TABLE 4B                                    __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 24 hr in vitro Exposure                                             Day 0      30 Min                                                                             5 Hr  Day 1                                                                              Day 2                                                                              Day 3                                                                             Day 4                                                                             Day 5                                 Treatment                                                                           L A  L A  L   A L  A L  A L A L A L A                                   __________________________________________________________________________    Cmpd 2                                                                              0 28 0 10 0   40                                                                              100                                                                              50                                                                              0   0                                                                              0 30                                                                              0  0                                                                              0 0                                         0 0  0 0  0   50                                                                              100                                                                              50                                                                              0  10                                                                              0 10                                                                              0 30                                                                              0 0                                   Cmpd 6                                                                              0 0  0 0  100 60                                                                              100                                                                              70                                                                              0  10                                                                              0 40                                                                              0 10                                                                              0 0                                         0 7  0 10 100 30                                                                              100                                                                              70                                                                              10 50                                                                              0 10                                                                              0  0                                                                              0 0                                   VC    0 0  0 0  0     0                                                                              0 10                                                                              0   0                                                                              0 10                                                                              0 10                                                                              0 0                                   __________________________________________________________________________

                                      TABLE 4C                                    __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 48 hr in vitro Exposure                                             Day 0      30 Min                                                                             5 Hr   Day 1 Day 2 Day 3                                                                             Day 4                                                                              Day 5                             Treatment                                                                           L A  L A  L   A  L  A  L  A  L A L A  L A                               __________________________________________________________________________    Cmpd 2                                                                              0 28 0 0  0   100                                                                              100                                                                              100                                                                              0  20 0 10                                                                              0 0  0 0                                     0 0  0 0  0    90                                                                              100                                                                              100                                                                              0  20 0  0                                                                              0 0  0 0                               Cmpd 6                                                                              0 1  0 20 100  90                                                                              100                                                                               90                                                                              25 80 0 90                                                                              0 10 0 0                                     0 7  0 20 100 100                                                                              100                                                                              100                                                                              90 100                                                                              0 30                                                                              0 30 0 0                               VC    0 0  0 0  0    0  0  0 0   0 0  0                                                                              0 0  0 0                               __________________________________________________________________________

                                      TABLE 5A                                    __________________________________________________________________________    Activity against Haemonchus contortus ("H"), Ostergia spp. ("O"),             Trichostrongylus colubriformis (T), and Nematodirus spp. ("NE")               Test 5: Evaluation of Varying Formulations and Doses of                       1,5-bis(4-(trifluromethyl)phenyl)-3-formazancarbonitrile                                Worm Eggs Per Gram of Feces (EPG)                                                                           % Worm                                               Days Following Treatment Egg              % Worm               Dose      Pre* 1    2    3    4    5-7* Reduction                                                                           Total Worm                                                                               Reductionp.1         Treatment                                                                           mg/kg                                                                             H/O  H/O  H/O  H/O  H/O  H/O  H/O   H T  O  NE H                    __________________________________________________________________________    Form- 5   6167/567                                                                           5800/500                                                                           0/0  0/0  0/0  0/0  100/100                                                                              0  0                                                                               0  17                                                                              100                  ulation A                                                                     Form- 5   1133/267                                                                            500/100                                                                           0/0  0/0  0/0  0/0  100/100                                                                              0  16                                                                             102                                                                               1                      ulation A                                                                     PEG 200                                                                             20  2967/400                                                                           2800/400                                                                           0/0  0/0  0/0  0/0  100/100                                                                              0  0                                                                              246                                                                               0 100                  Form.                                                                         PEG 200                                                                             20  3367/333                                                                           2700/200                                                                           0/0  0/0  0/0  0/0  100/100                                                                              0  0                                                                               61                                                                               0                      Form.                                                                         Form- 5   7467/567                                                                           3100/200                                                                           0/0  0/0  0/0  0/0  100/100                                                                              0  0                                                                              133                                                                               0 100                  ulation B                                                                     Form- 5   1367/233                                                                           700/0                                                                              0/0  0/0  0/0  0/0  100/100                                                                              0  0                                                                               89                                                                               0                      ulation B                                                                     VC    --  767/67                                                                             600/0                                                                              500/100                                                                            700/100                                                                            700/200                                                                            650/150                                                                            15/0  374                                                                              29                                                                               46                                                                              106                                                                              --                   __________________________________________________________________________     *Average of 3 days sampling                                                   .sup.1 At necropsy 7 days following treatment                            

                                      TABLE 5B                                    __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 24 hr in vitro Exposure                                                     Dose                                                                              Day 0                                                                              30 Min                                                                             5 Hr  Day 1                                                                              Day 2                                                                              Day 3 Day 4                                                                             Day 5                                                                              Day 6                    Treatment                                                                             mg/kg                                                                             L A  L A  L  A  L  A L  A L  A  L A L A  L A                      __________________________________________________________________________    Formulation A                                                                         5   0 20 0 0  100                                                                              80 100                                                                              90                                                                              100                                                                              50                                                                              0  0  0 20                                                                              0 0  0 0                      Formulation B                                                                         5   0 10 0 10 100                                                                              50 100                                                                              80                                                                              100                                                                              60                                                                              90 10 0 10                                                                              0 0  0  0                     PEG 200 Form.                                                                         20  0 0  0 10 100                                                                              90 100                                                                              60                                                                              100                                                                              60                                                                              0  20 0 50                                                                              0 0  0  0                     PEG 200 Form.                                                                         20  0 10 0 0  100                                                                              50 100                                                                              90                                                                              100                                                                              40                                                                              0  10 0  0                                                                              0 0  0  0                     Formulation B                                                                         5   0 0  0 0  100                                                                              100                                                                              100                                                                              40                                                                              100                                                                              70                                                                              0  0  0  0                                                                              0 0  0  0                     Formulation B                                                                         5   0 0  0 0  100                                                                              20 100                                                                              60                                                                              100                                                                              60                                                                              0  0  0 20                                                                              0 0  0  0                     VC          0 0  0 0   0 10  0 10                                                                               0 10                                                                              0  0  0  0                                                                              0 14 0  0                     __________________________________________________________________________

                                      TABLE 5C                                    __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 48 hr in vitro Exposure                                                     Dose                                                                              Day 0                                                                              30 Min                                                                            5 Hr  Day 1 Day 2 Day 3  Day 4                                                                              Day 5 Day 6                Treatment                                                                             mg/kg                                                                             L A  L A L  A  L  A  L  A  L   A  L  A L  A  L  A                 __________________________________________________________________________    Formulation A                                                                         5   0 20 0  0                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              0   80 0  20                                                                              0  4  0  0                 Formulation A                                                                         5   0 10 0 70                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100 100                                                                              90 50                                                                              15 54 10  34               PEG 200 Form.                                                                         20  0 0  0 70                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              0   90 0  50                                                                              0  0  0   0                PEG 200 Form.                                                                         20  0 10 0  0                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100 100                                                                              0   0                                                                              0  0  0   0                Formulation B                                                                         5   0 0  0 60                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              0    0 0  40                                                                              0  0  0   0                Formulation B                                                                         5   0 0  0 50                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100 90 0  40                                                                              0  0  0   4                VC          0 0  0  0                                                                               0  20                                                                               0  10                                                                               0  10                                                                              0    0 0   0                                                                              0  14 0   0                __________________________________________________________________________

                                      TABLE 6A                                    __________________________________________________________________________    Activity Against Haemonchus contortus ("H")                                   Test 6: Evaluation of Three Salts of 1,5-bis(4-(trifluoromethyl)phenyl)-3-    formazancarbonitrile                                                                   Worm Eggs Per Gram of Feces (EPG)                                                                      % Worm             Total                                                                              % Worm                           Days Following Treatment                                                                           Egg                Worm Re-                 Treat-                                                                             Dose                                                                              Pre*                                                                              1   2   3   4    5-7*                                                                              Reduction                                                                           Daily Worm Passage                                                                         Counts.sup.2                                                                       duction             ment mg/kg                                                                             H   H   H   H   H    H   H     H  H  H  Total.sup.1                                                                       H    H                   __________________________________________________________________________    Cmpd 8,                                                                            6.0 3100                                                                              1600                                                                               0  0   0    0   100    46                                                                               0 0   46 0    100                 Form I                                                                        Cmpd 8,                                                                            6.0 14500                                                                             13000                                                                             200 0   0    0   100   433                                                                              216                                                                              14 663 0    100                 Form I                                                                        Cmpd 10,                                                                           7.4 2425                                                                              3900                                                                              200 0   0    0   100                0    100                 Form J                                                                        Cmpd 10,                                                                           7.4 13400                                                                             13300                                                                             400 0   0    0   100   312                                                                              191                                                                              6  509 0    100                 Form J                                                                        Cmpd 13,                                                                           9.0 6550                                                                              6300                                                                              100 0   0    0   100   133                                                                               22                                                                              0  155 0    100                 Form K                                                                        Cmpd 13,                                                                           9.0 8650                                                                              9600                                                                               0  0   0    0   100   161                                                                               44                                                                              0  205 0    100                 Form K                                                                        VC   0    825                                                                               800                                                                              1100                                                                              900 1500 900  0     0  0 0   0  ND                       __________________________________________________________________________     Cmpd 8 = 1,5bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile             tetramethylammonium salt                                                      Cmpd 10 = 1,5bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile            tetran-propylammonium salt                                                    Cmpd 13 = 1,5bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile            trimethyloctadecylammonium salt                                               *Average of 3 days sampling                                                   .sup.1 Pieces of worm                                                         .sup.2 At necropsy 7 days following treatment                                 N/D = not determined                                                     

                                      TABLE 6B                                    __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 24 hr in vitro Exposure                                                      Dose                                                                              Day 0                                                                             30 Min                                                                            5 Hr Day 1 Day 2                                                                              Day 3                                                                              Day 4                                                                             Day 5                                                                              Day 6                      Treatment                                                                              mg/kg                                                                             L A L A L  A L  A  L  A L  A L A L A  L A                        __________________________________________________________________________    Cmpd 8, Form I                                                                         6.0 0 10                                                                              0 20                                                                              100                                                                              20                                                                              100                                                                              90 10 10                                                                              0  20                                                                              0 10                                                                              0 10 0 0                        Cmpd 8, Form I                                                                         6.0 0 20                                                                              0 10                                                                               0 40                                                                              100                                                                              90 10 20                                                                              0  50                                                                              0  0                                                                              0 10 0  10                      Cmpd 10, Form J                                                                        7.4 0 10                                                                              0 10                                                                               10                                                                              50                                                                              100                                                                              80 90 70                                                                              10  0                                                                              0  0                                                                              0 0  0  0                       Cmpd 10, Form J                                                                        7.4 0 10                                                                              0 30                                                                               10                                                                              20                                                                              100                                                                              80 10 20                                                                              0   0                                                                              0 10                                                                              0 0  0  0                       Cmpd 13, Form K                                                                        9.0 0 10                                                                              0 10                                                                              100                                                                              80                                                                              100                                                                              90 100                                                                              20                                                                              10 40                                                                              0 10                                                                              0 20 0  0                       Cmpd 13, Form K                                                                        9.0 0 10                                                                              0 10                                                                              100                                                                              80                                                                              100                                                                              100                                                                              100                                                                              90                                                                              80 30                                                                              0 30                                                                              0 0  0  10                      VC       0   0 10                                                                              0 30                                                                               0 20                                                                               0 10  0 20                                                                              0  30                                                                              0 10                                                                              0 0  0  0                       __________________________________________________________________________

                                      TABLE 6C                                    __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 24 hr in vitro Exposure                                                      Dose                                                                              Day 0                                                                             30 Min                                                                            5 Hr  Day 1 Day 2 Day 3                                                                              Day 4                                                                             Day 5                                                                             Day 6                     Treatment                                                                              mg/kg                                                                             L A L A L  A  L  A  L  A  L  A L A L A L A                       __________________________________________________________________________    Cmpd 8, Form I                                                                         6.0 0 10                                                                              0 30                                                                              100                                                                              100                                                                              100                                                                              100                                                                               10                                                                               90                                                                              0  30                                                                              0 20                                                                              0 30                                                                              0 10                      Cmpd 8, Form I                                                                         6.0 0 30                                                                              0 20                                                                               0  70                                                                              100                                                                              100                                                                               30                                                                               70                                                                              0  50                                                                              0 10                                                                              0 10                                                                              0  20                     Cmpd 10, Form J                                                                        7.4 0 30                                                                              0 30                                                                               10                                                                               90                                                                              100                                                                              100                                                                              100                                                                              100                                                                              10 60                                                                              0  0                                                                              0 30                                                                              0  40                     Cmpd 10, Form J                                                                        7.4 0 30                                                                              0 40                                                                               10                                                                               50                                                                              100                                                                              100                                                                               30                                                                              100                                                                              0   0                                                                              0 10                                                                              0 30                                                                              0  20                     Cmpd 13, Form K                                                                        9.0 0 30                                                                              0 20                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              10 90                                                                              0 40                                                                              0 40                                                                              0  20                     Cmpd 13, Form K                                                                        9.0 0 20                                                                              0 10                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              90 90                                                                              0 80                                                                              0 80                                                                              0  10                     VC       0   0 20                                                                              0 30                                                                               0  30                                                                               0  20                                                                               0  30                                                                              0  30                                                                              0 20                                                                              0 10                                                                              0  10                     __________________________________________________________________________

                                      TABLE 7A                                    __________________________________________________________________________    Activity Against Haemonchus contortus ("H"), Trichostrongylus                 colubriformis ("T"), and Ostertagia spp. ("O")                                Test 7: Evaluation of Three Salts of 1,5-bis(4-trifluromethyl)phenyl)-3-fo    rmazancarbonitrile                                                            __________________________________________________________________________                 Worm Eggs Per Gram of Feces (EPG)                                                   Days Following Treatment                                            Dose                                                                              Pre*  1      2     3       4        5-7*                         Treatment                                                                              mg/kg                                                                             H  T  H   T  H  T  H   T   H    T   H   T                        __________________________________________________________________________    Cmpd 11, Form L                                                                        8.13                                                                              1433                                                                             133                                                                              700 100                                                                               100                                                                              0 0   0   0    0   0   0                        Cmpd 11, Form L                                                                        8.13                                                                              6933                                                                              0 7100                                                                              200                                                                               200                                                                             200                                                                              0   500 0    700 0   666                      Cmpd 9, Form M                                                                         6.70                                                                              7933                                                                             266                                                                              4800                                                                              200                                                                               300                                                                             200                                                                              200 100 0    300 0   300                      Cmpd 9, Form M                                                                         6.70                                                                              1066                                                                             200                                                                              400  0   0                                                                               0 0   0   0    0   0   0                        Cmpd 12, Form N                                                                        8.85                                                                              1166                                                                             133                                                                              900 100                                                                               100                                                                             100                                                                              0   0   0    0   0   0                        Cmpd 12, Form N                                                                        8.85                                                                              1133                                                                             233                                                                              200 400                                                                                0                                                                              500                                                                              0   800 0    500 0   566                      VC       0   1133                                                                              0 1000                                                                               0 1100                                                                              0 900 0   1100 0   830 0                        __________________________________________________________________________                          % Worm Daily H. contortus                                                     Egg    Worm Passage                                                                            Total Worm                                                                              % Worm                                         Dose                                                                              Reduction                                                                            1  2 3    Counts.sup.1                                                                            Reduction                             Treatment                                                                              mg/kg                                                                             H  T   H  H H Total                                                                            H   T  O  H  T  O                      __________________________________________________________________________             Cmpd 11, Form L                                                                        8.13                                                                              100                                                                              100 46 13                                                                              0 59 0     0                                                                               0 100                                                                              100                                                                              --                              Cmpd 11, Form L                                                                        8.13                                                                              100                                                                              0   392                                                                              34                                                                              0 426                                                                              0   2000                                                                             719                                                                              100                                                                               0 0                               Cmpd 9, Form M                                                                         6.70                                                                              100                                                                              0   217                                                                              20                                                                              5 242                                                                              0    49                                                                               0 100                                                                              61 --                              Cmpd 9, Form M                                                                         6.70                                                                              100                                                                              100  8  0                                                                              0  8 0     2                                                                               0 100                                                                              98 --                              Cmpd 12, Form N                                                                        8.85                                                                              100                                                                              100 71 11                                                                              0 82 0    12                                                                              927                                                                              100                                                                              91 0                               Cmpd 12, Form N                                                                        8.85                                                                              100                                                                              0   21  0                                                                              0 21 0   1155                                                                             927                                                                              100                                                                               0 0                               VC       0    3 --   0  0                                                                              0  0 196  127                                                                             610                                                                               0  0 0                      __________________________________________________________________________     Cmpd 9 = 1,5bis(4-trifluromethyl)phenyl)-3-formazancarbonitrile               tetraethylammonium salt                                                       Cmpd 11 = 1,5bis(4-trifluromethyl)phenyl)-3-formazancarbonitrile              tetran-butylammonium salt                                                     Cmpd 12 = 1,5bis(4-trifluromethyl)phenyl)-3-formazancarbonitrile              tetran-pentylammonium salt                                                    *Average of 3 days sampling                                                   .sup.1 At necropsy 7 days following treatment                            

                                      TABLE 7B                                    __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 24 hr in vitro Exposure                                                      Dose                                                                              Day 0                                                                             30 Min                                                                            5 Hr  Day 1 Day 2                                                                              Day 3                                                                             Day 4                                                                             Day 5                           Treatment                                                                              mg/kg                                                                             L A L A L  A  L  A  L  A L A L A L A                             __________________________________________________________________________    Cmpd 11, Form L                                                                        8.13                                                                              0 10                                                                              0 30                                                                               60                                                                              50 100                                                                              80 0  20                                                                              0 20                                                                              0 20                                                                              0 10                            Cmpd 11, Form L                                                                        8.13                                                                              0 20                                                                              0 10                                                                              100                                                                              100                                                                              100                                                                              70 0  30                                                                              0 10                                                                              0 10                                                                              0  0                            Cmpd 9, Form M                                                                         6.70                                                                              0 20                                                                              0 20                                                                              100                                                                              90  90                                                                              60 0  40                                                                              0  0                                                                              0  0                                                                              0 20                            Cmpd 9, Form M                                                                         6.70                                                                              0 20                                                                              0  0                                                                              100                                                                              40 100                                                                              60 0  20                                                                              0  0                                                                              0 10                                                                              0 10                            Cmpd 12, Form N                                                                        8.85                                                                              0 10                                                                              0 10                                                                              100                                                                              90 100                                                                              100                                                                              90 70                                                                              0 20                                                                              0 10                                                                              0 10                            Cmpd 12, Form N                                                                        8.85                                                                              0 20                                                                              0 20                                                                              100                                                                              70 100                                                                              100                                                                              0  10                                                                              0  0                                                                              0 10                                                                              0 10                            VC       0   0 20                                                                              0  0                                                                               0 30  0 30 0  20                                                                              0 20                                                                              0 20                                                                              0 20                            __________________________________________________________________________

                                      TABLE 7C                                    __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 48 hr in vitro Exposure                                                      Dose                                                                              Day 0                                                                             30 Min                                                                            5 Hr  Day 1 Day 2 Day 3                                                                             Day 4                                                                             Day 5                          Treatment                                                                              mg/kg                                                                             L A L A L  A  L  A  L  A  L A L A L A                            __________________________________________________________________________    Cmpd 11, Form L                                                                        8.13                                                                              0 20                                                                              0 50                                                                               90                                                                              100                                                                              100                                                                              100                                                                               0 100                                                                              0 30                                                                              0 40                                                                              0 20                           Cmpd 11, Form L                                                                        8.13                                                                              0 30                                                                              0 20                                                                              100                                                                              100                                                                              100                                                                              100                                                                              10 70 0 20                                                                              0 20                                                                              0 20                           Cmpd 9, Form M                                                                         6.70                                                                              0 30                                                                              0 70                                                                              100                                                                              100                                                                              100                                                                              100                                                                               0 50 0  0                                                                              0 20                                                                              0 40                           Cmpd 9, Form M                                                                         6.70                                                                              0 30                                                                              0 30                                                                              100                                                                              100                                                                              100                                                                              100                                                                              10 70 0 50                                                                              0 10                                                                              0 10                           Cmpd 12, Form N                                                                        8.85                                                                              0 20                                                                              0 10                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              0 90                                                                              0 50                                                                              0 30                           Cmpd 12, Form N                                                                        8.85                                                                              0 30                                                                              0 20                                                                              100                                                                              100                                                                              100                                                                              100                                                                              40 70 0  0                                                                              0 30                                                                              0 10                           VC       0   0 30                                                                              0  0                                                                               0  40                                                                               0  30                                                                               0 20 0 30                                                                              0 20                                                                              0  0                           __________________________________________________________________________

                                      TABLE 8A                                    __________________________________________________________________________    Activity Against Haemonchus contortus ("H"), Trichostrongylus spp.            ("T"),                                                                        and Ostertagia spp. ("O")                                                     Test 8: Evaluation of 1,5-bis(4-trifluoromethyl)phenyl)-3-formazancarbonit    rile                                                                          trimethyloctadecylammonium salt Administered as an Oral Drench,               Formulation K                                                                 __________________________________________________________________________              Worm Eggs Per Gram of Feces (EPG)                                                    Days Following Treatment                                     Dose      Pre*   1       2      3      4       5-7*                           Treatment                                                                           mg/kg                                                                             H   T  H   T   H  T   H  T   H   T   H   T                          __________________________________________________________________________    Treated                                                                             9.0 3800                                                                              567                                                                              3300                                                                              800 200                                                                              300  0 300 0   400 0   400                        Treated                                                                             9.0 900 0  900 0   900                                                                              0   200                                                                              0   0   0   0   0                          VC    0   400 0  300 0   400                                                                              0   500                                                                              0   500 0   350 0                          __________________________________________________________________________                         % Worm                                                                        Egg   Daily Worm Passage   % Worm                                         Dose                                                                              Reduction                                                                           1   2 3 4  Total Worm Counts                                                                       Reduction                                Treatment                                                                            mg/kg                                                                            H  T  H   H H H  H    T O  H  T O                        __________________________________________________________________________               Treated                                                                             9.0 100                                                                              29.5                                                                             344 41                                                                              0 0  0    48                                                                              33 100                                                                              --                                                                              --                                  Treated                                                                             9.0 100                                                                              -- 215 26                                                                              0 0  0     5                                                                              26 100                                                                              --                                                                              --                                  VC    0    0 --  0   0                                                                              0 0  119  14                                                                              11 -- --                                                                              --                       __________________________________________________________________________     *Average of 3 days sampling                                              

                                      TABLE 8B                                    __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 24 hr in vitro Exposure                                             Dose      Day 0                                                                             30 Min                                                                             5 Hr Day 1                                                                              Day 2 Day 3                                                                              Day 4                                                                             Day 5                                                                              Day 6                        Treatment                                                                           mg/kg                                                                             L A L A  L  A L  A L   A L A  L A L A  L A                          __________________________________________________________________________    Treated                                                                             9.0 0 10                                                                              0 0  100                                                                              40                                                                              100                                                                              30                                                                              0   20                                                                              0 0  0 10                                                                              0 0  0 10                         Treated                                                                             9.0 0  0                                                                              0 0  100                                                                              10                                                                              100                                                                              70                                                                              100 70                                                                              0 20 0 10                                                                              0 0  0   0                        VC    0   0 10                                                                              0 10  0 40                                                                               0 20                                                                              0   20                                                                              0 0  0 10                                                                              0 20 0  20                        __________________________________________________________________________

                                      TABLE 8C                                    __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 48 hr in vitro Exposure                                             Dose      Day 0                                                                             30 Min                                                                             5 Hr  Day 1 Day 2  Day 3                                                                             Day 4                                                                             Day 5                                                                             Day 6                       Treatment                                                                           mg/kg                                                                             L A L A  L  A  L  A  L   A  L A L A L A L A                         __________________________________________________________________________    Treated                                                                             9.0 0 20                                                                              0 0  100                                                                              100                                                                              100                                                                              100                                                                              0   70 0 10                                                                              0 20                                                                              0 10                                                                              0 10                        Treated                                                                             9.0 0 10                                                                              0 0  100                                                                              100                                                                              100                                                                              100                                                                              100 100                                                                              0 90                                                                              0 50                                                                              0 20                                                                              0   0                       VC    0   0 20                                                                              0 10  0  20                                                                               0  30                                                                              0   20 0 10                                                                              0 30                                                                              0 20                                                                              0  20                       __________________________________________________________________________

                                      TABLE 9A                                    __________________________________________________________________________    Activity Against Haemonchus contortus ("H"), Trichostrongylus spp.            ("T"),                                                                        and Ostertagia spp. ("O")                                                     Test 9: Evaluation of 1,5-bis(4-trifluoromethyl)phenyl)-3-formazancarbonit    rile                                                                          Administered Daily for Seven Days at 1.0 mg/kg/day, by Intraruminal           Injection, Formulation F                                                      __________________________________________________________________________    Worm Eggs Per Gram of Feces (EPG)                                                          Days Following Treatment                                         Pre*         1      2     3     4      5-7*   8-10                            Treatment                                                                           H   T  H   T  H  T  H  T  H   T  H   T  H   T                           __________________________________________________________________________    Treated                                                                             1050                                                                              200                                                                              1000                                                                              100                                                                              400                                                                              100                                                                              300                                                                               0 0   200                                                                              0    0 0   0                           Treated                                                                             500 150                                                                              300 100                                                                              200                                                                              100                                                                               0 200                                                                              0    0 0   100                                                                              0   0                           VC    400 150                                                                              400 200                                                                              300                                                                              100                                                                              400                                                                              100                                                                              500 100                                                                              367 100                                                                              360 200                         __________________________________________________________________________    % Worm                                                                        Egg              Daily Worm Passage                                                                          Total      % Worm                              Reduction        1  2  3       Worm Counts.sup.1                                                                        Reduction                           Treatment                                                                           H     T    H  H  H  Total                                                                              H    T  O  H    T   O                          __________________________________________________________________________    Treated                                                                             100   100  6  67 8  81    11**                                                                               0 46 86.4 100 0                          Treated                                                                             100   100  0  41 3  44    0   17 46 100   10 0                          VC    12.5  33.3 0   0 0   0   66   19 27 --   --  --                         __________________________________________________________________________     *Average of 3 days sampling                                                   **10 males, 1 female                                                     

                                      TABLE 9B                                    __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 24 hr in vitro Exposure                                             Day 0      Day 1                                                                             Day 2                                                                             Day 3                                                                             Day 4                                                                              Day 5                                                                              Day 6                                                                              Day 7                                                                              Day 8                                                                             Day 9                                                                             Day 10                     Treatment                                                                           L A  L A L A L A L  A L A  L A  L  A L A L A L A                        __________________________________________________________________________    Treated                                                                             0 0  25                                                                              10                                                                              10                                                                              0 85                                                                              0 100                                                                              10                                                                              60                                                                              10 75                                                                              10 60 30                                                                              0 20                                                                              0 0 0 0                        Treated                                                                             0 10 60                                                                              10                                                                              90                                                                              0 10                                                                              0 100                                                                              20                                                                              75                                                                              0  75                                                                              0  100                                                                              60                                                                              0 30      0                                                                             0                                                                             0                                                                             0                        VC    0 0   0                                                                                0                                                                              0                                                                              0  0                                                                              0  0  0                                                                               0                                                                              0   0                                                                              0   0  0                                                                              0  0      0                                                                             0                                                                             0                                                                             0                        __________________________________________________________________________

                                      TABLE 9C                                    __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 48 hr in vitro Exposure                                                    Day 0                                                                             Day 1                                                                              Day 2 Day 3 Day 4 Day 5                                                                              Day 6 Day 7                                                                              Day 8                                                                             Day                                                                                Day 10             Treatment                                                                            L A L  A L  A  L  A  L  A  L  A L  A  L  A L A L A  L A                __________________________________________________________________________    Treated                                                                              0 10                                                                              100                                                                              80                                                                              100                                                                              60 100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              20                                                                              100                                                                              100                                                                              100                                                                              80                                                                              0 20                                                                              0 0  0 0                Treated                                                                              0 10                                                                              100                                                                              80                                                                              100                                                                              100                                                                              75 80 100                                                                              100                                                                              100                                                                              50                                                                              100                                                                               80                                                                              100                                                                              80                                                                              0 60       0                                                                             10                                                                            0                                                                             0                VC     0  0                                                                                0                                                                              10                                                                               10                                                                              10  0 20  0  20                                                                               0  0                                                                               0  0  0 0  0                                                                              0        0                                                                             0                                                                             0                                                                             0                __________________________________________________________________________

                                      TABLE 10A                                   __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 24 hr in vitro Exposure                                             Test 10: Evaluation of 1,5-bis(4-trifluoromethyl)phenyl)-3-formazancarboni    trile                                                                         tetra-n-butylammonium salt in Blood From Non-Wormy Sheep Treated With         Formulation G                                                                 Dose      Day 0                                                                             30 Min                                                                            5 Hr Day 1                                                                              Day 2                                                                             Day 3                                                                             Day 4                                                                             Day 5                                                                             Day 6                             Treatment                                                                           mg/kg                                                                             L A L A L  A L  A L A L A L A L A L A                               __________________________________________________________________________    Treated                                                                             8.13                                                                              0 0 0 0 100                                                                              40                                                                              100                                                                              30                                                                              0 10                                                                              0 10                                                                              0 0 0 10                                                                              0 0                               Treated                                                                             8.13                                                                              0 0 0 0 100                                                                              50                                                                              100                                                                              10                                                                              0  0                                                                              0 20                                                                              0 0 0 20                                                                              0  0                              VC    0   0 0 0 0  0  0                                                                               0 10                                                                              0 10                                                                              0  0                                                                              0 0 0 10                                                                              0  0                              __________________________________________________________________________

                                      TABLE 10B                                   __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 48 hr in vitro Exposure                                             Dose      Day 0                                                                             30 Min                                                                            5 Hr  Day 1 Day 2                                                                             Day 3                                                                              Day 4                                                                              Day 5                                                                             Day 6                         Treatment                                                                           mg/kg                                                                             L A L A L  A  L  A  L A L A  L A  L A L A                           __________________________________________________________________________    Treated                                                                             8.13                                                                              0 0 0 0 100                                                                              100                                                                              100                                                                              100                                                                              0 10                                                                              0 0  0 0  0 10                                                                              0 0                           Treated                                                                             8.13                                                                              0 0 0 0 100                                                                              100                                                                              100                                                                              100                                                                              0  0                                                                              0 20 0 0  0 20                                                                              0  10                         VC    0   0 0 0 0  0  10                                                                               0  20                                                                              0 10                                                                              0 0  0 10 0 10                                                                              0  0                          __________________________________________________________________________

TESTS AGAINST FASCIOLA HEPATICA IN SHEEP (Tests 11-13 and Tables 11-13)

The present invention was also evaluated for the control of Fasciolahepatica (liver fluke) in sheep. Sheep approximately twelve months oldwere each experimentally infected by a single intraruminal injection of100 metacercariae of Fasciola hepatica. The sheep were alloted totreatment or control groups, two or three per group, and given eitherthe test compound or the vehicle. Treated animals received the testcompound at each of day 3, 3 weeks, and 12 weeks after fluke infection.Administration of the test compound was by a single intraruminalinjection. The control group received a single intraruminal injection ofthe vehicle at 12 weeks.

Blood samples were collected prior to treatment and daily for five daysafter the 3 week and 12 week treatment. These samples were analyzed foractivity against Phormia regina and Stomoxys calcitrans according to theprocedure described above. At 14 weeks after fluke infection, all sheepwere euthanized and analyzed for total worm counts.

The results of several tests are set forth in the following tables.

                                      TABLE 11A                                   __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans                                                                    ("A") Following 24 hr in vitro Exposure                                       Test 11: Evaluation of 1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbon    itrile,                                                                       PEG 200 Formulation                                                           Dose      Day 0                                                                              Day 1 Day 2                                                                              Day 3                                                                             Day 4                                                                              Day 5                                      Treatment.sup.1                                                                     mg/kg                                                                             L A  L  A  L  A L A L A  L A                                        __________________________________________________________________________    Treated                                                                             5   0 0  100                                                                               90                                                                              75 40                                                                              0 0 0 0  0 0                                        Treated                                                                             5   0 0  100                                                                               80                                                                              75 40                                                                              0 0 0 10 0 0                                        Treated                                                                             10  0 0  100                                                                              100                                                                              0  10                                                                              0 0 0 0  0 0                                        Treated                                                                             10  0 10 100                                                                              100                                                                              0   0                                                                              0 0 0 0  0 10                                       VC    0   0 0   0  0 0   0                                                                              0 0 0 0  0 0                                        __________________________________________________________________________

                                      TABLE 11B                                   __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 48 hr in vitro Exposure                                             Dose      Day 0                                                                              Day 1 Day 2                                                                              Day 3                                                                             Day 4                                                                              Day 5                                      Treatment.sup.1                                                                     mg/kg                                                                             L A  L  A  L  A L A L A  L A                                        __________________________________________________________________________    Treated                                                                             5   0 0  100                                                                              100                                                                              100                                                                              100                                                                             0 60                                                                              0 50 0 40                                       Treated                                                                             5   0 0  100                                                                              100                                                                              100                                                                              100                                                                             25                                                                              80                                                                              0 50 0 20                                       Treated                                                                             10  0 0  100                                                                              100                                                                               75                                                                              100                                                                             0 30                                                                              0 20 0 40                                       Treated                                                                             10  0 20 100                                                                              100                                                                               75                                                                              100                                                                             0 90                                                                              0 60 0 10                                       VC    0   0 10  0  20                                                                               0  20                                                                             0 20                                                                              0 20 0 20                                       __________________________________________________________________________     .sup.1 3 weeks after experimental fluke infection                        

                                      TABLE 11C                                   __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans                                                                    ("A") Following 24 hr in vitro Exposure                                       Dose      Day 0                                                                             Day 1                                                                              Day 2                                                                              Day 3 Day 4 Day 5                                     Treatment.sup.1                                                                     mg/kg                                                                             L A L  A L  A L   A L   A L   A                                     __________________________________________________________________________    Treated                                                                             5   0 0 100                                                                              60                                                                              100                                                                              40                                                                              100 70                                                                              100 20                                                                              100 0                                     Treated                                                                             5   0 0 100                                                                              10                                                                              100                                                                              10                                                                              0   20                                                                              0   0 0   0                                     Treated                                                                             10  0 0 100                                                                              70                                                                              100                                                                              40                                                                              100 10                                                                              0   10                                                                              0   0                                     Treated                                                                             10  0 0 100                                                                              60                                                                              100                                                                              20                                                                              0   30                                                                              0   0 0   0                                     VC    0   0 0  0 20                                                                               0  0                                                                              0   20                                                                              0   0 0   0                                     VC    0   0 0  0 10                                                                               0  0                                                                              0    0                                                                              0   0 0   0                                     __________________________________________________________________________

                                      TABLE 11D                                   __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 48 hr in vitro Exposure                                             Dose      Day 0                                                                              Day 1 Day 2 Day 3  Day 4 Day 5                                 Treatment.sup.1                                                                     mg/kg                                                                             L A  L  A  L  A  L   A  L A   L   A                                 __________________________________________________________________________    Treated                                                                             5   0 0  100                                                                              100                                                                              100                                                                              100                                                                              100 100                                                                              100 90                                                                              100 100                               Treated                                                                             5   0 10 100                                                                              100                                                                              100                                                                               90                                                                              0    0 0   10                                                                              0   0                                 Treated                                                                             10  0 0  100                                                                               90                                                                              100                                                                              100                                                                              100 30 10  30                                                                              0   0                                 Treated                                                                             10  0 0  100                                                                              100                                                                              100                                                                              100                                                                              0   30 0   10                                                                              0   0                                 VC    0   0 0   0  20                                                                               0  0 0   20 0    0                                                                              0   0                                 VC    0   0 10  0  10                                                                               0   0                                                                              0    0 0   20                                                                              0   0                                 __________________________________________________________________________     .sup.1 12 weeks after experimental fluke infection                       

                                      TABLE 11E                                   __________________________________________________________________________    Activity Against Fasciola hepatica                                            Dose     Egg % Liver                                                                            Total Worm Counts.sup.1                                     (mg/kg)                                                                           Dose PI                                                                            Fecal                                                                             Damage                                                                             BD LD Total                                                                             Comments                                          __________________________________________________________________________    10  3 days                                                                             -   20   0  16 16  Muddy appearance of bile sac content.             10  3 days                                                                             +   90   6  13 19  Liver 25% consolidated; rest granulated.           5  3 wks                                                                              -    8   0  10 10  Little damage to liver; consolidated.              5  3 wks                                                                              +   25   10 27 37  Diffused liver damage                             10  3 wks                                                                              +   25   16 16 36  Liver damage consolidated.                        10  3 wks                                                                              +   50   9   4 13  Enlarged bile duct; pus in liver ducts;                                       liver                                                                         damage consolidated.                               5  12                                                                              wks                                                                              -   45   0   0  0  2 abscesses and 2 nodules in liver; great                                     amt                                                                           of pus and ropy excrement in liver ducts.                                     Diffused liver damage.                             5  12                                                                              wks                                                                              -   75   0    6                                                                               6  Pus in liver ducts; dead worms; liver damage                                  consolidated.                                     10  12                                                                              wks                                                                              -   20   0   9  9  Diffused liver damage; live worms.                10  12                                                                              wks                                                                              +   30   1  11 12  Ropy excrement; live worms in ducts of                                        liver;                                                                        consolidated liver damage.                         0       +   25   9  16 25  Liver damage diffused.                             0       +   55   8  21 29  Consolidated liver damage.                        __________________________________________________________________________     .sup.1 Necropsy 14 weeks after experimental fluke infection.                  BD = bile duct                                                                LD = liver ducts                                                              PI = post infection                                                      

A second test was conducted. The procedures were the same as thosepreviously described except as follows: Formulation H was used; it wasadministered only twice, at 7 days and 3 weeks after fluke infection;and the animals were euthanized and total worm counts determined at 10weeks after fluke infection. The results were as set forth in thefollowing tables.

                                      TABLE 12A                                   __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans                                                                    ("A") Following 24 hr in vitro Exposure                                       Test 12: Evaluation of 1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbon    itrile,                                                                       Formulation H                                                                 Dose      Day 0                                                                             Day 1                                                                              Day 2                                                                              Day 3                                                                              Day 4                                                                              Day 5                                       Treatment.sup.1                                                                     mg/kg                                                                             L A L  A L  A L  A L  A L   A                                       __________________________________________________________________________    Treated                                                                             5   0 0 100                                                                              60                                                                              100                                                                              70                                                                               25                                                                              60                                                                               40                                                                               0                                                                              0   10                                      Treated                                                                             5   0 0 100                                                                              80                                                                              100                                                                              90                                                                              100                                                                              30                                                                               60                                                                              30                                                                              25  30                                      Treated                                                                             10  0 0 100                                                                              90                                                                              100                                                                              70                                                                              100                                                                              40                                                                              100                                                                              50                                                                              100 70                                      Treated                                                                             10  0 0 100                                                                              70                                                                              100                                                                              60                                                                              100                                                                              60                                                                              100                                                                              40                                                                              10  50                                      VC    0   0 0  0  0                                                                               0  0                                                                               0  0                                                                               0  0                                                                              0    0                                      VC    0   0 0  0  0                                                                               0  0                                                                               0  0                                                                               0  0                                                                              0    0                                      __________________________________________________________________________

                                      TABLE 12B                                   __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 48 hr in vitro Exposure                                             Dose      Day 0                                                                              Day 1 Day 2 Day 3 Day 4 Day 5                                  Treatment.sup.1                                                                     mg/kg                                                                             L A  L  A  L  A  L  A  L  A  L   A                                  __________________________________________________________________________    Treated                                                                             5   0 0  100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              80 0   20                                 Treated                                                                             5   0 0  100                                                                              100                                                                              100                                                                               90                                                                              100                                                                               90                                                                              100                                                                              90 25  70                                 Treated                                                                             10  0 0  100                                                                              100                                                                              100                                                                              100                                                                              100                                                                               90                                                                              100                                                                              90 100 100                                Treated                                                                             10  0 10 100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              20  50                                 VC    0   0 10  0  0  0  0  0  0  0  0 0    0                                 VC    0   0 0   0  0   0                                                                               0  0  0  0  0 0    0                                 __________________________________________________________________________     .sup.1 Blood samples taken beginning at day 7 post fluke infection       

                                      TABLE 12C                                   __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 24 hr in vitro Exposure                                             Dose      Day 0                                                                             Day 1 Day 2 Day 3 Day 4 Day 5                                   Treatment.sup.1                                                                     mg/kg                                                                             L A L  A  L  A  L  A  L   A L   A                                   __________________________________________________________________________    Treated                                                                             5   0  0                                                                              100                                                                               90                                                                              100                                                                              90 100                                                                              70 10  20                                                                              0    0                                  Treated                                                                             5   0 20                                                                              100                                                                              100                                                                              100                                                                              90  90                                                                              80 0   10                                                                              0   20                                  Treated                                                                             5   0 10                                                                              100                                                                               80                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100 80                                                                              100 80                                  Treated                                                                             10  0  0                                                                              100                                                                              100                                                                              100                                                                              90 100                                                                              90 0   10                                                                              0   10                                  Treated                                                                             10  0  0                                                                              100                                                                              100                                                                              100                                                                              80 100                                                                              90 90  40                                                                              80  40                                  Treated                                                                             10  0 20                                                                              100                                                                              100                                                                              100                                                                              80 100                                                                              60 0   20                                                                              0    0                                  VC    0   0 10                                                                               0  10                                                                               0  0  0 30 0   10                                                                              0    0                                  VC    0   0 20                                                                               0  20                                                                               0 10  0 10 0    0                                                                              0    0                                  __________________________________________________________________________

                                      TABLE 12D                                   __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 48 hr in vitro Exposure                                             Dose      Day 0                                                                             Day 1 Day 2 Day 3 Day 4 Day 5                                   Treatment.sup.1                                                                     mg/kg                                                                             L A L  A  L  A  L  A  L  A  L   A                                   __________________________________________________________________________    Treated                                                                             5   0 30                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              30 100                                                                              10  90                                  Treated                                                                             5   0 30                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              10 100                                                                              0   70                                  Treated                                                                             5   0 20                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100 100                                 Treated                                                                             10  0  0                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              10 60 0   10                                  Treated                                                                             10  0 10                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              90 90  90                                  Treated                                                                             10  0 30                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              10 80 0   20                                  VC    0   0 10                                                                               0  20                                                                               0  10                                                                               0  40                                                                               0 20 0   10                                  VC    0   0 30                                                                               0  30                                                                               0  30                                                                               0  20                                                                               0  0 0   20                                  __________________________________________________________________________     .sup.1 Blood samples taken beginning at 3 weeks post fluke infection     

                  TABLE 12E                                                       ______________________________________                                        Activity Against Fasciola hepatica                                                               Total Worm Counts                                          Test  Dose              % Liver                                                                              Im-                                            Group (mg/kg)  Dose PI  Damage mature                                                                              Mature                                                                              Total                              ______________________________________                                        1     5        7     days 50     2     11    13                                     5        7     days 10     0      0     0                               2     10       7     days 20     7      0     7                                     10       7     days 10     0     11    11                               3     5        3     wks  10     1     11    12                                     5        3     wks  10     0     10    10                                     5        3     wks  25     10    10    20                               4     10       3     wks  10     16     0    16                                     10       3     wks  10     10     0    10                                     10       3     wks  25     6      2     8                               5     0        --       15     0      7     7                                       0        --       10     1     12    13                                 ______________________________________                                         .sup.1 Necropsy 10 weeks after experimental fluke infection.                  PI = post infection                                                      

A third test was conducted. The procedures were the same as previouslydescribed except as follows. Formulation R was used; it was administeredat 7 days, 3 weeks, and 10 weeks after fluke infection. The results wereas set forth in the following tables.

                  TABLE 13A                                                       ______________________________________                                        Data on Liver Damage and Number of Flukes                                     Found at Necropsy                                                             Test 13: Evaluation of                                                        1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile                     trimethyloctadecylammonium salt, at 36 mg/kg, Formulation R                                 Total Worm Counts.sup.1                                         Dose           % Liver  Im-                Fecal                              (mg/kg)                                                                             Dose PI  Damage   mature Mature                                                                              Total Sample                             ______________________________________                                        36    7     days   50     22      3    25    -                                36    7     days   35     11     39    50    +                                36    7     days   40     12      0    12    -                                36    3     wks    75     18     26    44    -                                36    3     wks    40     15     14    29    -                                36    3     wks    20      4     79    83    +                                36    10    wks    15      0      0     0    -                                36    10    wks    75     13      0    13    -                                36    10    wks    20      0     16    16    -                                VC    0            65     20     19    39    -                                VC    0            40      0     31    31    -                                VC    0            90     19      1    20    -                                ______________________________________                                         .sup.1 Necropsy 10 weeks after experimental fluke infection.                  PI =  post infection                                                     

                  TABLE 13B                                                       ______________________________________                                        Percent Insecticidal Activity Against Phormia regina ("L")                    and Stomoxys calcitrans ("A") Following 24 hr                                 in vitro Exposure (7 Days P.I.)                                               Dose  Day 0   Day 1     Day 2  Day 3 Day 4 Day 5                              mg/kg L     A     L    A    L    A   L   A   L   A   L                                                     A                                                ______________________________________                                        36    0     0     100  100   75  70  0   20  0   10  0                                                     20                                                                            36 0 0 100 90  0  0 0 20 0 10 0 20                                            36 0 0 100 90 100 70 0  0 0 30 0 30              ______________________________________                                    

                  TABLE 13C                                                       ______________________________________                                        Percent Insecticidal Activity Against Phormia regina ("L")                    and Stomoxys calcitrans ("A") Following 48 hr                                 in vitro Exposure (7 Days P.I.)                                               Dose                                                                          mg/  Day 0   Day 1     Day 2   Day 3 Day 4 Day 5                              kg   L     A     L    A    L    A    L   A   L   A   L                                                     A                                                ______________________________________                                        36   0     30    100  100   90  100  0   50  0   30  0                                                     20                                                                            36 0 10 100 100  0  70 0 20 0 50 0 20                                         36 0  0 100 100 100 100 0 60 0 30 0 40           ______________________________________                                    

                  TABLE 13D                                                       ______________________________________                                        Percent Insecticidal Activity Against Phormia regina ("L")                    and Stomoxys calcitrans ("A") Following 24 hr                                 in vitro Exposure (3 Wks P.I.)                                                Dose  Day 0   Day 1     Day 2  Day 3 Day 4 Day 5                              mg/kg L     A     L    A    L   A    L   A   L   A   L                                                     A                                                ______________________________________                                        36    0     0     100  100  0   0    10  0   20  0   0                                                     0                                                                             36 10 0 100 100 10 0 10 0 10 0 0 0                                            36 0 0 40 90 20 100 0 0 10 0 0 0                 ______________________________________                                    

                  TABLE 13E                                                       ______________________________________                                        Percent Insecticidal Activity Against Phormia regina ("L")                    and Stomoxys calcitrans ("A") Following 24 hr                                 in vitro Exposure (3 Wks P.I.)                                                Dose                                                                          mg/  Day 0   Day 1     Day 2   Day 3 Day 4 Day 5                              kg   L     A     L    A    L    A    L   A   L   A   L                                                     A                                                ______________________________________                                        36   20    0     100  100  60   0    20  0   30  0   20                                                    0                                                                             36 10 0 100 100 10 0 40 0 20 0 20 0                                           36  0 0 100 100 100 100 10 0 30 0 10 0           ______________________________________                                    

                  TABLE 13F                                                       ______________________________________                                        Percent Insecticidal Activity Against Phormia regina ("L")                    and Stomoxys calcitrans ("A") Following 24 hr                                 in vitro Exposure (10 Wks P.I.)                                               Dose  Day 0   Day 1     Day 2  Day 3 Day 4 Day 5                              mg/kg L     A     L    A    L    A   L   A   L   A   L                                                     A                                                ______________________________________                                        36    0     10    100  100  20   20  0    0  0   20  0                                                     20                                                                            36 0  0 100 90 0 30 0  0 0 10 0 10                                            36 0 10 100 80 0 10 0  0 0 30 0 10                                            0 (VC) 0 20  0 10 0 10 0 10 0 10 0 20                                         0 (VC) 0 20  0 20 0 20 0 10 0 10 0 30                                         0 (VC) 0 10  0 30 0  0 0 30 0 10 0 20            ______________________________________                                    

                                      TABLE 13G                                   __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A") Following 48 hr in vitro Exposure (10 Wks P.I.)              Dose Day 0                                                                             Day 1   Day 2    Day 3                                                                             Day 4                                                                             Day 5                                       mg/kg                                                                              L A L   A   L    A   L A L A L A                                         __________________________________________________________________________    36   0 30                                                                              100 100 100  90  0 70                                                                              0 30                                                                              0 40                                        36   0 10                                                                              100 100 0    60  0  0                                                                              0 20                                                                              0 10                                        36   0 10                                                                              100 100 60   100 0 10                                                                              0 30                                                                              0 10                                        0 (VC)                                                                             0 30                                                                               0   10 0    50  0 40                                                                              0 20                                                                              0 30                                        0 (VC)                                                                             0 30                                                                               0   30 0    20  0 20                                                                              0 20                                                                              0 70                                        0 (VC)                                                                             0 30                                                                               0   30 0    20  0 50                                                                              0 10                                                                              0 30                                        __________________________________________________________________________

TESTS IN CATTLE (Tests 14-25 and Tables 14-25)

Numerous evaluations were conducted in cattle generally averaging about300 kg in weight. In Tests 14-19, there was no helminth infection. Bloodsamples were collected via the jugular vein at multiple times, typicallythe following: prior to compound administration, at 30 minutes, 5 hoursand 24 hours after compound administration, and daily thereafter up to12 days after compound administration. These blood samples wereevaluated for control of Phormia regina and Stomoxys calcitrans by thetest procedure described above.

In Tests 20-25, the compound administration and blood sampling were asdescribed above, but the cattle were infected with Ostertagia ostertagi,and the cattle were additionally evaluated for control of this species.This evaluation was made by determining the number of worm eggs/gram offeces, both prior to compound administration and daily after compoundadministration. Those animals exhibiting greater than 75 percentreduction in eggs/gram of feces were euthanized and total worm countsdetermined on necropsy and compared to nontreated controls.

Results are set forth in the following tables.

                                      TABLE 14A                                   __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 24 hr in vitro Exposure                                             Test 14: Evaluation of 1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbon    itrile                                                                        In Cattle, Administered Subcutaneously Using Formulations C, D, and E                   Dose                                                                              Day 0                                                                              30 Min                                                                             5 Hr Day 1                                                                             Day 2                                                                             Day 3                                                                             Day 4                                                                              Day 5                                                                              Day 6                      Treatment.sup.1                                                                         mg/kg                                                                             L A  L A  L A  L A L A L A L A  L A  L A                        __________________________________________________________________________    Formulation C                                                                           10  0 0  0 0  0 10 0 0 0 10                                                                              0 20                                                                              0 0  0 0  0 0                        Formulation C                                                                           10  0 0  0 20 0 0  0 0 0 10                                                                              0 20                                                                              0 0  0 0  0  0                       Formulation D                                                                           10  0 0  0 20 0 0  0 0 0 10                                                                              0 20                                                                              0 10 0 14 0  24                      Formulation D                                                                           10  0 0  0 10 0 0  0 0 0  0                                                                              0 20                                                                              0 0  0 0  0  0                       Formulation E                                                                           10  0 0  0 0  0 0  0 0 0 20                                                                              0  0                                                                              0 0  0 0  0  0                       Formulation E                                                                           10  0 0  0 0  0 0  0 0 0 10                                                                              0 10                                                                              0 0  0 0  0  0                       Vehicle of Form C                                                                       --  0 0  0 0  0 0  0 0 0 10                                                                              0  0                                                                              0 0  0 0  0  0                       Vehicle of Form D                                                                       --  0 10 0 0  0 10 0 0 0 10                                                                              0 10                                                                              0 20 0 4  0  0                       Vehicle of Form E                                                                       --  0 0  0 0  0 0  0 0 0  0                                                                              0  0                                                                              0 0  0 14 0  0                       __________________________________________________________________________     .sup.1 Single subcutaneous dose of 10 mg/kg in left upper neck in front o     shoulder.                                                                

                                      TABLE 15A                                   __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 24 hr in vitro Exposure                                             Test 15: Evaluation of 1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbon    itrile                                                                        In Cattle, Administered Intraruminally Using Formulation F                            Dose                                                                              Day 0                                                                             30 Min                                                                            5 Hr Day 1                                                                              Day 2                                                                              Day 3                                                                             Day 4                                                                              Day 6                             Treatment                                                                             mg/kg                                                                             L A L A L  A L  A L  A L A L A  L A                               __________________________________________________________________________    Formulation F                                                                         10  0 0 0 20                                                                              100                                                                              30                                                                              100                                                                              80                                                                              100                                                                              20                                                                              0 40                                                                              0 50 0 10                              Formulation F                                                                         10  0 0 0 20                                                                              100                                                                              30                                                                              100                                                                              90                                                                              75 50                                                                              0 30                                                                              0 0  0 10                              VC       0  0 0 0  0                                                                               0  0                                                                               0  0                                                                               0 10                                                                              0 10                                                                              0 0  0  0                              __________________________________________________________________________

                                      TABLE 15B                                   __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 48 hr in vitro Exposure                                                     Dose                                                                              Day 0                                                                             30 Min                                                                            5 Hr  Day 1 Day 2 Day 3                                                                             Day 4                                                                              Day 6                          Treatment                                                                             mg/kg                                                                             L A L A L  A  L  A  L  A  L A L A  L A                            __________________________________________________________________________    Formulation F                                                                         10  0 0 0 20                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              0 40                                                                              0 50 0 40                           Formulation F                                                                         10  0 0 0 20                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              90 0 30                                                                              0 0  0 20                           VC       0  0 0 0  0                                                                               0  0  0  0  0 10 0 10                                                                              0 0  0  0                           __________________________________________________________________________

                                      TABLE 16A                                   __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 24 hr in vitro Exposure                                             Test 16: Evaluation of 1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbon    itrile                                                                        tetra-n-butylammonium salt In Cattle Administered Intraruminally Using        Formulation G                                                                         Dose                                                                              Day 0                                                                              30 Min                                                                            5 Hr Day 1                                                                              Day 2                                                                              Day 3                                                                             Day 4                                                                             Day 5                             Treatment                                                                             mg/kg                                                                             L A  L A L A  L  A L  A L A L A L A                               __________________________________________________________________________    Formulation G                                                                         16.26                                                                             0 0  0 0 90                                                                              60 100                                                                              40                                                                              10 10                                                                              0 0 0 20                                                                              0 0                               Formulation G                                                                         16.26                                                                             0 20 0 0 40                                                                              0  100                                                                              30                                                                              0  10                                                                              0 0 0 10                                                                              0 20                              VC      0   0 0  0 0  0                                                                              0   0  0                                                                              0   0                                                                              0 0 0 20                                                                              0 0                               __________________________________________________________________________

                                      TABLE 16B                                   __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 48 hr in vitro Exposure                                                     Dose                                                                              Day 0                                                                              30 Min                                                                             5 Hr Day 1 Day 2                                                                              Day 3                                                                              Day 4                                                                              Day 5                         Treatment                                                                             mg/kg                                                                             L A  L A  L  A L  A  L  A L  A L A  L A                           __________________________________________________________________________    Formulation G                                                                         16.26                                                                             0 0  0 0  100                                                                              90                                                                              100                                                                              100                                                                              0  30                                                                              0  0 0 10 0 10                          Formulation G                                                                         16.26                                                                             0 20 0 10 100                                                                              80                                                                              100                                                                              90 10 30                                                                              30 0 0 0  0 10                          VC      0   0 0  0 0   0 10                                                                               0  0 0   0                                                                              0  0 0 0  0  0                          __________________________________________________________________________

                                      TABLE 17A                                   __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 24 hr in vitro Exposure                                             Test 17: Evaluation of Salts of 1,5-bis(4-(trifluoromethyl)phenyl)-3-forma    zancarbonitrile                                                               In Cattle Administered Intraruminally Using Formulations I, J, and K                      Dose                                                                              Day 0                                                                             30 Min                                                                            5 Hr  Day 1                                                                              Day 2 Day 3                                                                              Day 4                                                                             Day 5                                                                             Day                                                                               Day 7               Treatment   mg/kg                                                                             L A L A L  A  L  A L  A  L A  L A L A L A L A                 __________________________________________________________________________    Cmpd 8, Form I                                                                            11.9                                                                              0  0                                                                              0 20                                                                              60 0  100                                                                              90                                                                              0  0  0 0  0 0 0 0 0 0 0 0                 Cmpd 8, Form I                                                                            11.9                                                                              0 10                                                                              0 30                                                                              60 40 100                                                                              60                                                                              90 30 0 0  0 0 0 0 0      0                                                                      0      0                Cmpd 10, Form J                                                                           14.8                                                                              0  0                                                                              0 10                                                                              10 0   90                                                                              60                                                                              0  0  0 0  0 0 0 0 0      0                                                                      0      0                Cmpd 10, Form J                                                                           14.8                                                                              0 10                                                                              0 40                                                                              100                                                                              0  100                                                                              80                                                                              15 0  0 10 0 0 0 0 0      0                                                                      0      0                Cmpd 13, Form K                                                                           18  0 10                                                                              0 40                                                                              25 40 100                                                                              70                                                                              100                                                                              70 0 0  0 0 0 0 0      0                                                                      0      0                Cmpd 13, Form K                                                                           18  0 10                                                                              0 10                                                                              90 50 100                                                                              90                                                                              100                                                                              90 0 10 0 0 0 0 0      0                                                                      0      10               Vehicle of Form I-K                                                                       0   0  0                                                                              0  0                                                                               0 0   0  0                                                                              0  0  0 0  0 0 0 0 0      0                                                                      0      0                __________________________________________________________________________     Cmpd 8 = 1,5bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile             tetramethylammonium salt                                                      Cmpd 10 = 1,5bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile            tetran-propylammonium salt                                                    Cmpd 13 = 1,5bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile            trimethyloctadecylammonium salt                                          

                                      TABLE 17B                                   __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 48 hr in vitro Exposure                                                         Dose                                                                              Day 0                                                                             30 Min                                                                            5 Hr  Day 1 Day 2  Day 3                                                                             Day 4                                                                             Day 5                                                                             Day                                                                               Day 7              Treatment   mg/kg                                                                             L A L A L  A  L  A  L  A   L A L A L A L A L A                __________________________________________________________________________    Cmpd 8, Form I                                                                            11.9                                                                              0 20                                                                              0 30                                                                              100                                                                              70 100                                                                              100                                                                              100                                                                              90  0  0                                                                              0 0 0 0 0 0 0 0                Cmpd 8, Form I                                                                            11.9                                                                              0 20                                                                              0 30                                                                              100                                                                              90 100                                                                               90                                                                              100                                                                              90  0  0                                                                              0 0 0 0 0      0                                                                      0      0               Cmpd 10, Form J                                                                           14.8                                                                              0  0                                                                              0 10                                                                              100                                                                              80 100                                                                              100                                                                               75                                                                              80  0 20                                                                              0 0 0 0 0      0                                                                      0      0               Cmpd 10, Form J                                                                           14.8                                                                              0 10                                                                              0 60                                                                              100                                                                              80 100                                                                              100                                                                              100                                                                              80  0 30                                                                              0 0 0 0 0      0                                                                      0      0               Cmpd 13, Form K                                                                           18  0 10                                                                              0 40                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100 0 30                                                                              0 0 0 0 0      0                                                                      0      0               Cmpd 13, Form K                                                                           18  0 10                                                                              0 30                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100 0 10                                                                              0 0 0 0 0      0                                                                      0      20              Vehicle of Form I-K                                                                       0   0  0                                                                              0  0                                                                               0 20  0  0  0  0  0 10                                                                              0 0 0 0 0      0                                                                      0      0               __________________________________________________________________________

                                      TABLE 18A                                   __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 24 hr in vitro Exposure                                             Test 18: Evaluation of Sodium Salt of 1,5-bis(4-(trifluoromethyl)phenyl)-3    -formazancarbonitrile (Cmpd 7)                                                In Cattle Administered Subcutaneously Using PEG 200 Formulation               Dose      Blood                                                                             Day 0                                                                              30 Min                                                                            5 Hr Day 1                                                                              Day 2                                                                              Day 3                                                                             Day 4                                                                             Day 5                                                                              Day 6                      Treatment                                                                           mg/kg                                                                             Sample                                                                            L A  L A L A  L A  L A  L A L A L A  L A                        __________________________________________________________________________    Cmpd 7                                                                              1.0 WB  0 0  0  0                                                                              0 0  0 0  0 0  0 0 0 10                                                                              0 0  0 0                        Cmpd 7    S   0 0  0  0                                                                              0 0  0 10 0 10 0 0 0  0                                                                              0 0     0                                                                       0                             Cmpd 7                                                                              1.0 WB  0 0  0 10                                                                              0 0  0 0  0 0  0 0 0  0                                                                              0 10    0                                                                       10                            Cmpd 7    S   0 0  0 10                                                                              0 0  0 10 0 0  0 0 0  0                                                                              0 10    0                                                                       0                             Cmpd 7                                                                              2.0 WB  0 0  0  0                                                                              0 0  0 10 0 0  0 0 0 10                                                                              0 0     0                                                                       0                             Cmpd 7    S   0 0  0 10                                                                              0 0  0 0  0 0  0 0 0 10                                                                              0 0     0                                                                       0                             Cmpd 7                                                                              2.0 WB  0 10 0  0                                                                              0 0  0 0  0 20 0 0 0 10                                                                              0 20    0                                                                       0                             Cmpd 7    S   0 0  0 10                                                                              0 10 0 0  0 0  0 0 0  0                                                                              0 10    0                                                                       0                             VC    0   WB  0 0  0 10                                                                              0 0  0 10 0 0  0 0 0 10                                                                              0 0     0                                                                       0                             VC        S   0 0  0  0                                                                              0 10 0 10 0 10 0 0 0  0                                                                              0 0     0                                                                       0                             __________________________________________________________________________      WB = whole blood                                                             S = serum                                                                

                                      TABLE 18B                                   __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 48 hr in vitro Exposure                                             Dose      Blood                                                                             Day 0                                                                             30 Min                                                                            5 Hr                                                                              Day 1                                                                             Day 2                                                                              Day 3                                                                             Day 4                                                                             Day 5                                                                             Day 6                          Treatment                                                                           mg/kg                                                                             Sample                                                                            L A L A L A L A L A  L A L A L A L A                            __________________________________________________________________________    Cmpd 7                                                                              1.0 WB  0 20                                                                              0  0                                                                              0  0                                                                              0  0                                                                              0 10 0 20                                                                              0 10                                                                              0 10                                                                              0 0                            Cmpd 7    S   0  0                                                                              0  0                                                                              0 10                                                                              0 30                                                                              0 0  0 10                                                                              0 40                                                                              0 30   0                                                                        0                                Cmpd 7                                                                              1.0 WB  0  0                                                                              0 10                                                                              0  0                                                                              0  0                                                                              0 0  0  0                                                                              0  0                                                                              0 20   0                                                                        10                               Cmpd 7    S   0 10                                                                              0 30                                                                              0 10                                                                              0 40                                                                              0 0  0 10                                                                              0  0                                                                              0 30   0                                                                        0                                Cmpd 7                                                                              2.0 WB  0  0                                                                              0 10                                                                              0 10                                                                              0 10                                                                              0 0  0  0                                                                              0 20                                                                              0 20   0                                                                        0                                Cmpd 7    S   0  0                                                                              0 30                                                                              0 20                                                                              0 30                                                                              0 20 0 10                                                                              0 40                                                                              0 20   0                                                                        0                                Cmpd 7                                                                              2.0 WB  0 10                                                                              0  0                                                                              0 10                                                                              0 10                                                                              0 20 0  0                                                                              0 20                                                                              0 20   0                                                                        30                               Cmpd 7    S   0 10                                                                              0 10                                                                              0 20                                                                              0 20                                                                              0 0  0 50                                                                              0  0                                                                              0 30   0                                                                        0                                VC    0   WB  0  0                                                                              0 20                                                                              0 10                                                                              0 20                                                                              0 0  0  0                                                                              0 20                                                                              0 10   0                                                                        0                                VC        S   0 10                                                                              0  0                                                                              0 20                                                                              0 10                                                                              0 0  0  0                                                                              0 10                                                                              0 10   0                                                                        0                                __________________________________________________________________________

                                      TABLE 18C                                   __________________________________________________________________________    Examination of Subcutaneous Injection Sites for Seven Days Following          Treatment of Calves                                                           Dose      Size.sup.1 and State of Injection Site Swelling                     Treatment                                                                           mg/kg                                                                             Day 2  Day 3    Day 4     Day 5     Day 6     Day                   __________________________________________________________________________                                                            7                     Cmpd 7                                                                              1.0 5.2 × 7.6 (S)                                                                  7.6 × 7.6 (SF)                                                                    7.6 × 10.3 (SF)                                                                   7.6 × 10.3 (SF)                                                                   7.6 × 10.3                                                                       7.6 × 15                                                                (F)                   Cmpd 7                                                                              1.0 5.2 × 7.6 (S)                                                                  7.6 × 7.6 (SF)                                                                   7.6 × 7.6 (SF)                                                                    7.6 × 7.6 (SF)                                                                    7.6 × 7.6                                                                         7.6 × 7.6                                                               (F)                   Cmpd 7                                                                              2.0 5.2 × 7.6 (S)                                                                  7.6 × 7.6 (SF)                                                                   7.6 × 7.6 (SF)                                                                    7.6 × 7.6 (SF)                                                                    7.6 × 7.6                                                                         7.6 × 7.6                                                               (F)                   Cmpd 7                                                                              2.0 5.2 × 7.6 (S)                                                                  7.6 × 7.6 (SF)                                                                   7.6 × 7.6 (SF)                                                                    7.6 × 7.6 (SF)                                                                    7.6 × 7.6                                                                         7.6 × 7.6                                                               (F)                   VC                                                                            VC    none                                                                              none   none     none      none      none                            __________________________________________________________________________     .sup.1 cm × cm                                                          F = firm                                                                      S = soft                                                                      SF = soft perimeter, firm center                                         

                                      TABLE 19A                                   __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 24 hr in vitro Exposure                                             Test 19: Evaluation of 1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbon    itrile                                                                        trimethyloctadecylammonium salt (Cmpd 13), In Cattle, Administered            Subcutaneously,                                                               Dissolved in DMSO, 80 mg/ml                                                                 Dose                                                                              Blood                                                                             Pre  30 Min                                                                            5 Hr                                                                              Day 1                                                                              Day 2                                                                             Day 3                                                                              Day 4                        Treatment     mg/kg                                                                             Sample                                                                            L A  L A L A L A  L A L A  L A                          __________________________________________________________________________    Cmpd 13       1.0 WB  0 10 0  0                                                                              0  0                                                                              0 10 0 10                                                                              0 0  0 20                         Cmpd 13           S   0 0  0 30                                                                              0 20                                                                              0 0  0 10                                                                              0 10 0 10                         Cmpd 13       1.0 WB  0 0  0  0                                                                              0  0                                                                              0 0  0 10                                                                              0 0  0  0                         Cmpd 13           S   0 0  0  0                                                                              0 10                                                                              0 0  0  0                                                                              0 20 0 10                         Cmpd 13       2.0 WB  0 0  0 10                                                                              0 10                                                                              0 0  0 10                                                                              0 0  0 10                         Cmpd 13           S   0 10 0 30                                                                              0 10                                                                              0 20 0  0                                                                              0 0  0 10                         Cmpd 13       2.0 WB  0 10 0 10                                                                              0  0                                                                              0 0  0  0                                                                              0 0  0  0                         Cmpd 13           S   0 0  0  0                                                                              0  0                                                                              0 0  0 10                                                                              0 10 0  0                         Oxfendazole.sup.1 (ref. standard)                                                           10.0                                                                              WB  0 0  0  0                                                                              0 20                                                                              0 0  0 10                                                                              0 0  0  0                         Oxfendazole.sup.1 (ref. standard)                                                               S   0 0  0  0                                                                              0 10                                                                              0 10 0  0                                                                              0 0  0 10                         Oxfendazole.sup.1 (ref. standard)                                                           10.0                                                                              WB  0 10 0 10                                                                              0  0                                                                              0 20 0 10                                                                              0 0  0 10                         Oxfendazole.sup.1 (ref. standard)                                                               S   0 0  0  0                                                                              0 20                                                                              0 0  0 10                                                                              0 20 0  0                         Vehicle (DMSO)                                                                              0   WB  0 0  0 10                                                                              0  0                                                                              0 0  0 10                                                                              0 10 0  0                         Vehicle (DMSO)    S   0 0  0 10                                                                              0 10                                                                              0 10 0  0                                                                              0 0  0  0                         __________________________________________________________________________     .sup.1 Single intraruminal injection                                          S = serum                                                                     WB = whole blood                                                         

                                      TABLE 19B                                   __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 48 hr in vitro Exposure                                                           Dose                                                                              Blood                                                                             Pre 30 Min                                                                            5 Hr                                                                              Day 1                                                                             Day 2                                                                             Day 3                                                                             Day 4                           Treatment     mg/kg                                                                             Sample                                                                            L A L A L A L A L A L A L A                             __________________________________________________________________________    Cmpd 13       1.0 WB  0 10                                                                              0 10                                                                              0 10                                                                              0 10                                                                              0 10                                                                              0 10                                                                              0 30                            Cmpd 13           S   0  0                                                                              0 30                                                                              0 20                                                                              0 10                                                                              0 10                                                                              0 10                                                                              0 10                            Cmpd 13       1.0 WB  0 10                                                                              0  0                                                                              0 10                                                                              0 10                                                                              0 20                                                                              0  0                                                                              0 10                            Cmpd 13           S   0 10                                                                              0 10                                                                              0 20                                                                              0  0                                                                              0 10                                                                              0 30                                                                              0 20                            Cmpd 13       2.0 WB  0  0                                                                              0 10                                                                              0 20                                                                              0 10                                                                              0 10                                                                              0 20                                                                              0 20                            Cmpd 13           S   0 20                                                                              0 60                                                                              0 20                                                                              0 50                                                                              0 20                                                                              0 10                                                                              0 20                            Cmpd 13       2.0 WB  0 20                                                                              0 10                                                                              0  0                                                                              0 10                                                                              0  0                                                                              0 10                                                                              0  0                            Cmpd 13           S   0 10                                                                              0  0                                                                              0  0                                                                              0  0                                                                              0 20                                                                              0 20                                                                              0  0                            Oxfendazole.sup.1 (ref. standard)                                                           10.0                                                                              WB  0  0                                                                              0 10                                                                              0 50                                                                              0 20                                                                              0 20                                                                              0  0                                                                              0 10                            Oxfendazole.sup.1 (ref. standard)                                                               S   0  0                                                                              0  0                                                                              0 10                                                                              0 20                                                                              0  0                                                                              0  0                                                                              0 10                            Oxfendazole.sup.1 (ref. standard)                                                           10.0                                                                              WB  0 10                                                                              0 20                                                                              0 10                                                                              0 30                                                                              0 10                                                                              0 10                                                                              0 20                            Oxfendazole.sup.1 (ref. standard)                                                               S   0  0                                                                              0 20                                                                              0 30                                                                              0  0                                                                              0 10                                                                              0 20                                                                              0 20                            Vehicle (DMSO)                                                                              0   WB  0 10                                                                              0 10                                                                              0 10                                                                              0  0                                                                              0 20                                                                              0 10                                                                              0  0                            Vehicle (DMSO)    S   0  0                                                                              0 10                                                                              0 10                                                                              0 10                                                                              0 10                                                                              0 10                                                                              0  0                            __________________________________________________________________________

                                      TABLE 19C                                   __________________________________________________________________________    Examination of Subcutaneous Injection Sites for Six Days Following            Treatment of Calves                                                                    Dose Size.sup.1 and State of Injection Site Swelling                 Treatment                                                                              mg/kg                                                                              Day 1                                                                             Day 2   Day 3   Day 4   Day 6                               __________________________________________________________________________    Cmpd 13  1.0  0   7.8 × 10.5 (S)                                                                  7.8 × 10.5 (S)                                                                  7.8 × 10.5 (F)                                                                  .sup. 7.8 × 10.5 (SF)         Cmpd 13  1.0  0   7.8 × 15.1 (S)                                                                  7.8 × 10.5 (S)                                                                  7.8 × 15.1 (F)                                                                  7.8 × 10.5 (F)                Cmpd 13  2.0  0   0       0       7.8 × 10.5 (F)                                                                  7.8 × 15.6 (F)                Cmpd 13  2.0  0   0       0       7.8 × 10.5 (F)                                                                  7.8 × 20.1 (F)                Vehicle (DMSO)                                                                VC       0    0   0       0       0                                           __________________________________________________________________________     .sup.1 cm × cm                                                          F = firm                                                                      S = soft                                                                 

                                      TABLE 20A                                   __________________________________________________________________________    Helminthologic Data                                                           Test 20: Evaluation of 1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbon    itrile In Cattle,                                                             Administered Intraruminally ("IR") or Subcutaneously ("SC"),                  Using Formulation In Ethanol and Polyethylene Glycol 200                                 Worm Eggs Per Gram of Feces                                                      Days Following Treatment                                                                              % Worm Egg                                                                            Total Worm                            Dose Pre*                                                                             1  2  3  4  5-7*                                                                             9  11 14 Reduction                                                                             Counts.sup.1                    Treatment                                                                           (mg/kg)                                                                            OST                                                                              OST                                                                              OST                                                                              OST                                                                              OST                                                                              OST                                                                              OST                                                                              OST                                                                              OST                                                                              OST     OST                             __________________________________________________________________________    Treated                                                                             10                                                                              IR 667                                                                              300                                                                              700                                                                              500                                                                              500                                                                              450                                                                              300                                                                              100                                                                              400                                                                              40.0    N/D                                   10                                                                              SC 333                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              300                                                                              100                                                                              69.9    N/D                                   10                                                                              SC 533                                                                              200                                                                              200                                                                              300                                                                              300                                                                              150                                                                              100                                                                              100                                                                              100                                                                              81.2    291                                   10                                                                              SC 367                                                                              400                                                                              300                                                                              300                                                                              300                                                                              450                                                                              200                                                                              300                                                                              400                                                                              0       N/D                             VC    0 SC.sup.2                                                                         367                                                                              500                                                                              500                                                                              500                                                                              500                                                                              500                                                                              300                                                                              300                                                                              400                                                                              0       N/D                             __________________________________________________________________________     *Average of 3 days sampling                                                   **Euthanized 15 days post treatment                                           .sup.1 At necropsy 7 days following treatment                                 .sup.2 Single subcutaneous injection of 20 ml ethanol + 30 ml PEG 200.        N/D = not done                                                                OST = Ostertagia ostertagi                                               

                                      TABLE 20B                                   __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 24 hr in vitro Exposure                                                    Dose  Day 0                                                                              30 Min                                                                            5 Hr                                                                              Day 1                                                                             Day 2                                                                             Day 3                                                                             Day 4                                                                             Day 5                                                                             Day 6                                                                             Day 9                                                                             Day                                                                               Day 14              Treatment                                                                            mg/kg L  A L A L A L A L A L A L A L A L A L A L A L A                 __________________________________________________________________________    Treated                                                                              10                                                                              (IR)                                                                              0  0 0 0 0 0 0 0 0 10                                                                              0 0 0 0 0 0 0 0 0 0 0 0 0 0                 Treated                                                                              10                                                                              (SC)                                                                              0  10                                                                              0 0 0 0 0 0 0 10                                                                              0 10                                                                              0 0 0 0       0                                                                             10                                                                            0                                                                             0 0 0 0 0                 Treated                                                                              10                                                                              (SC)                                                                              0  0 0 0 0 0 0 0 0 0 0 0 0 20                                                                              0 0       0                                                                             0                                                                             0                                                                             0 0 0 0 0                 Treated                                                                              10                                                                              (SC)                                                                              0  0 0 0 0 20                                                                              0 30                                                                              0 0 0 0 0 10                                                                              0 0       0                                                                             0                                                                             0                                                                             10                                                                              0 0 0 0                 VC           0  10                                                                              0 0 0 0 0 0 0 0 0 0 0 10                                                                              0 0       0                                                                             0                                                                             0                                                                             10                                                                              0 0 0 0                 __________________________________________________________________________

                                      TABLE 20C                                   __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 48 hr in vitro Exposure                                                    Dose Day 0                                                                             30 Min                                                                            5 Hr  Day 1                                                                             Day 2                                                                             Day 3                                                                             Day 4                                                                             Day 5                                                                              Day 6                                                                             Day 9                                                                             Day                                                                               Day 14             Treatment                                                                            mg/kg                                                                              L A L A L  A  L A L A L A L A L A  L A L A L A L A                __________________________________________________________________________    Treated                                                                              10                                                                              (IR)                                                                             0  0                                                                              0 12                                                                              0  90 0 90                                                                              0  2                                                                              0 18                                                                              0  0                                                                              0 0  0 60                                                                              0 12                                                                              0 10                                                                              0 12               Treated                                                                              10                                                                              (SC)                                                                             0 12                                                                              0  0                                                                              0  2  0 60                                                                              0 60                                                                              0 50                                                                              0 60                                                                              0 0        0                                                                             60                                                                            0                                                                             22                                                                              0 22                                                                              0 60               Treated                                                                              10                                                                              (SC)                                                                             0 12                                                                              0 12                                                                              10 0  0 50                                                                              0 60                                                                              0 18                                                                              0 60                                                                              0 50       0                                                                             00                                                                            12                                                                              0  2                                                                              0  2               Treated                                                                              10                                                                              (SC)                                                                             0 12                                                                              0  0                                                                              30 2  0 90                                                                              0 90                                                                              0 50                                                                              0 60                                                                              0 90       0                                                                             70                                                                            0                                                                             80                                                                              0 70                                                                              0 70               VC          0 12                                                                              0 12                                                                              0  2  0  0                                                                              0  0                                                                              0  2                                                                              0  0                                                                              0 2        0                                                                             00                                                                            12                                                                              0 12                                                                              0  0               __________________________________________________________________________

                  TABLE 20D                                                       ______________________________________                                        Examination of Subcutaneous Injection Sites                                   Eleven Days Following Treatment of Calves                                                       Diameter                                                                      Size                                                        Treatment                                                                              Swelling (cm)     State                                              ______________________________________                                        Treated (IR)                                                                           No       --         --                                               Treated (SC)                                                                           Yes      7.8      Soft exterior; hard center                         Treated (SC)                                                                           Yes      6.4      Soft exterior; hard center                         Treated (SC)                                                                           Yes      4.0      Soft exterior; hard center                         Control (SC)                                                                           No       --         --                                               ______________________________________                                    

                                      TABLE 21A                                   __________________________________________________________________________    Test 21: Evaluation of 1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbon    itrile (Cmpd 6)                                                               and its Tetraethylammonium Salt (Cmpd 9), Administered by Several             Routes,                                                                       PEG 200 Formulations                                                          Helminthologic Data                                                                  Dose  Worm Eggs Per Gram of Feces                                             mg/kg &   Days Following Treatment                                                                          % Worm Egg                                      Route of                                                                            Pre*                                                                              1   2   3   4   5-7*                                                                              Reduction Total Worm                                                                            % Worm                 Treatment                                                                            Admin OST OST OST OST OST OST OST       Counts.sup.1                                                                          Reduction              __________________________________________________________________________    Cmpd 6 40 IR 200 300 200 300 200 250 0         1756    0                      Cmpd 6 40 IR 300 100 200 200 200 200 33.3       658    51.6                   Cmpd 9 10 SC 200 300 300 200 100 250 0          840    38.2                   Cmpd 9 10 SC 400 300 300 300 100 275 31.2      2482    0                      Cmpd 6 1.0                                                                              IV 400 DIED                                                         VC     0  SC 200 400 300 200 300 250 0         1360    --                     __________________________________________________________________________     *Average of 3 days sampling                                                   .sup.1 At necropsy 7 days following treatment                                 IR = intraruminal                                                             IV = intravenous                                                              OST = Ostertagia spp.                                                         SC = subcutaneous                                                        

                                      TABLE 21B                                   __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 24 hr in vitro Exposure                                             Dose      Day 0 30 Min                                                                              5 Hr  Day 1 Day 2 Day 3 Day 4 Day 5 Day 7               Treatment                                                                           mg/kg                                                                             L  A  L  A  L  A  L  A  L  A  L  A  L  A  L  A  L  A                __________________________________________________________________________    Cmpd 6                                                                              40                                                                              IR                                                                              0   0  0 10  0 10  0 20  0  0  0  0 0  10 0  10 0   0               Cmpd 6                                                                              40                                                                              IR                                                                              0   0  0  0  0  0 100                                                                              50  0  0  0 10 0   0 0  10     0                                                                      10                                  (10)                                                             Cmpd 9                                                                              10                                                                              SC                                                                              0   0  0 10  0 10  0  0  0  0  0  0 0   0 0   0     0                                                                       0                                  (10)                                                             Cmpd 9                                                                              10                                                                              SC                                                                              0   0  0  0 25 10  0 10 90 20 10 10 0   0 0   0     0                                                                       0                     Cmpd 6                                                                              1.0                                                                             IV                                                                              0   0 25 50 10 10 DIED                                              VC    0 SC                                                                              0   0  0  0  0  0  0  0  0 10  0  0 0   0 0   0 0   0               __________________________________________________________________________     (no.) actual mortality before adjustment                                 

                                      TABLE 21C                                   __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 48 hr in vitro Exposure                                             Dose      Day 0                                                                              30 Min                                                                              5 Hr  Day 1 Day 2 Day 3 Day 4 Day 5 Day 7                Treatment                                                                           mg/kg                                                                             L A  L  A  L  A  L  A  L  A  L  A  L  A  L  A  L  A                 __________________________________________________________________________    Cmpd 6                                                                              40                                                                              IR                                                                              0 10  0 10  0 80  90                                                                              100                                                                               0 20  0  0  0 10 0  10 0   0                            (60)  (30)  (80)        (70)  (10)  (30)  (10)   (30)             Cmpd 6                                                                              40                                                                              IR                                                                              0  0  0  0  0 10 100                                                                              90   0                                                                              40  0 10  0 10 0   0     0                                                                      20                                  (50)  (10)  (60)        (90)  (40)  (60)  (30)   (70)             Cmpd 9                                                                              10                                                                              SC                                                                              0  0  0 10  0 10  0 70  0 90  0  0  0  0 0   0     0                                                                       0                                  (10)  (20)  (10)        (90)  (20)  (30)  (30)   (20)             Cmpd 9                                                                              10                                                                              SC                                                                              0  0  0  0 100                                                                              80  0 90 100                                                                              90 25 40 25  0 0   0     0                                                                      30                                  (50)  (80)                          (50)  (40)   (80)             Cmpd 6                                                                              1.0                                                                             IV                                                                              0  0 60 90  10                                                                              80 DIED                                                           (10)                                                              VC    0 SC                                                                              0 20  0 20  0  0  0  0  0 40  0 10  0  0 0   0     0                                                                       0                                  (70)  (70)  (50)  (50)  (90)  (60)  (10)  (30)   (50)             __________________________________________________________________________

                  TABLE 21D                                                       ______________________________________                                        Examination of Subcutaneous Injection Sites                                   Ten Days After Treatment of Calves                                            Treatment Swelling   Diameter Size (cm)                                                                          State                                      ______________________________________                                        Cmpd 9    Yes        15            Firm                                       Cmpd 9    Yes        7.5           Soft                                       VC        No         --            --                                         ______________________________________                                    

                  TABLE 22A                                                       ______________________________________                                        Test 22: Evaluation of Salts of                                               1,5-bis(4-(trifluoromethyl)phenyl)-3-                                         formazancarbonitrile in Cattle Administered                                   Intraruminally Using Formulations L, M, and N                                 Helminthologic Data                                                                   Worm Eggs Per       % Worm                                                    Gram of Feces (EPG) Egg                                               Dose             Days Following Treatment                                                                         Re-                                       Treat- mg/    Pre*   1    2    3    4    10*  duction                         ment   kg     OST    OST  OST  OST  OST  OST  OST                             ______________________________________                                        Cmpd 11,                                                                             16.26   350    300  0     0   400 300  14.3                            Form L                                                                        Cmpd 11,                                                                             16.26   700    200  0     0   200 500  28.6                            Form L                                                                        Cmpd 9,                                                                              13.40  1050    400 400    0   400 300  71.4                            Form M                                                                        Cmpd 9,                                                                              13.40  1050    500  0     0   400 300  71.4                            Form M                                                                        Cmpd 12,                                                                             17.70   650    300  0     0   100 100  76.9                            Form N                                                                        Cmpd 12,                                                                             17.70   400    200 100    0   500 200  50.0                            Form N                                                                        VC     0      1250   1800 900  1100 1100 900  12.0                            ______________________________________                                         Cmpd 9 = 1,5bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile             tetraethylammonium salt                                                       Cmpd 11 = 1,5bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile            tetran-butylammonium salt                                                     Cmpd 12 = 1,5bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile            tetran-pentylammonium salt                                                    *Average of 3 days sampling                                                   OST = Ostertagia ostertagi                                               

                                      TABLE 22B                                   __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 24 hr in vitro Exposure                                                       Dose Day 0  30 Min                                                                              5 Hr  Day 1   Day 2  Day 3                        Treatment mg/kg                                                                              L  A   L  A  L  A  L   A   L   A  L  A                         __________________________________________________________________________    Cmpd 11, Form L                                                                         16.26                                                                              0  0   0   0 0  0   0  30   90 20 0  0                         Cmpd 11, Form L                                                                         16.26                                                                              0  0   0   0 0  20 100 100 100 50 0  0                         Cmpd 9, Form M                                                                          13.40                                                                              0  0   0  20 10 0  10  30   10 20 0  0                         Cmpd 9, Form M                                                                          13.40                                                                              0  0   0  10 0  0  100 60  100 60 0  10                        Cmpd 12, Form N                                                                         17.70                                                                              0  0   0  20 0  0  60  100 100 90 0  0                         Cmpd 12, Form N                                                                         17.70                                                                              0  0   0  10 0  20 50  60  100 90 0  0                         VC        0    0  10  0  20 0  0  20   0   0  10 0  20                        __________________________________________________________________________

                                      TABLE 22C                                   __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 48 hr in vitro Exposure                                                       Dose Day 0 30 Min                                                                              5 Hr   Day 1   Day 2   Day 3                       Treatment mg/kg                                                                              L  A  L  A  L  A   L   A   L   A   L  A                        __________________________________________________________________________    Cmpd 11, Form L                                                                         16.26                                                                              0   0 0  10  0  10  0   90 100 100 0  20                       Cmpd 11, Form L                                                                         16.26                                                                              0   0 0  10 75 100 100 100 100 100 0  30                       Cmpd 9, Form M                                                                          13.40                                                                              0  20 0  20 10  90  30 100  10  60 0  10                       Cmpd 9, Form M                                                                          13.40                                                                              0   0 0  10  0  30 100 100 100  90 0  30                       Cmpd 12, Form N                                                                         17.70                                                                              0  10 0  30  0  60  90 100 100 100 0  80                       Cmpd 12, Form N                                                                         17.70                                                                              0   0 0  10  0  20  90 100 100 100 0  20                       VC        0    0  20 0  20  0  20  0   20  0   10 0  20                       __________________________________________________________________________

                                      TABLE 23A                                   __________________________________________________________________________    Test 23: Evaluation in Cattle of 1,5-bis(4-(trifluoromethyl)phenyl)-3-form    azancarbonitrile                                                              trimethyloctadecylammonium salt (Cmpd 13) Alone and in Combination With       Oxfendazole,                                                                  Administered Intraruminally, Formulations O and P                             Helminthologic Data                                                                            Worm Eggs Per Gram of Feces (EPG)                                                                     % Worm                                                    Days Following Treatment                                                                          Egg    Total Worm                                                                            % Worm                            Dose Pre*                                                                              1   2   3   4   5-7*                                                                              Reduction                                                                            Counts.sup.1                                                                          Reduction             Treatment   mg/kg                                                                              OST OST OST OST OST OST OST    OST     OST                   __________________________________________________________________________    Cmpd 13 + oxfendazole                                                                     18 + 10                                                                            1750                                                                               300                                                                                0   0   0   0 100    0       100                   Cmpd 13 + oxfendazole                                                                     18 + 10                                                                            1300                                                                               100                                                                                0   0   0   0 100    0       100                   Cmpd 13     18   1300                                                                              1300                                                                              1400                                                                              1200                                                                              1100                                                                              1375                                                                               0     N/D     N/D                   Cmpd 13     18    500                                                                               500                                                                               600                                                                               500                                                                               700                                                                               600                                                                               0     N/D     N/D                   VC           0    500                                                                               500                                                                               500                                                                               400                                                                               600                                                                               500                                                                               0     N/D     N/D                   __________________________________________________________________________     *Average of 3 days sampling                                                   .sup.1 At necropsy 7 days following treatment                                 N/D = not determined                                                          OST = Ostertagia ostertagi                                               

                                      TABLE 23B                                   __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 24 hr in vitro Exposure                                                                  Day 30  5    Day   Day  Day   Day   Day                              Dose Blood                                                                             0   Min Hr   1     2    3     4     5                    Treatment   mg/kg                                                                              Sample                                                                            L A L A L  A L  A  L  A L  A  L  A  L  A                 __________________________________________________________________________    Cmpd 13 + oxfendazole                                                                     18 + 10                                                                            WB  0  0                                                                              0  0                                                                               0 40                                                                              40 10 30 30                                                                              40 10  0 20 0  10                Cmpd 13 + oxfendazole                                                                     18 + 10                                                                            S   0  0                                                                              0  0                                                                              40 20                                                                              100                                                                              90 100                                                                              80                                                                              100                                                                              30 100                                                                              90 0  20                Cmpd 13 + oxfendazole                                                                     18 + 10                                                                            WB  0 20                                                                              0 30                                                                               0 10                                                                              80  0 80 10                                                                              40 20  0  0 0   0                Cmpd 13 + oxfendazole                                                                     18 + 10                                                                            S   0 10                                                                              0  0                                                                              90 30                                                                              100                                                                              100                                                                              100                                                                              90                                                                              100                                                                              60 100                                                                              70 0  20                Cmpd 13     18   WB  0 10                                                                              0 10                                                                               0  0                                                                               0 10  0  0                                                                               0 10  0  0 0   0                Cmpd 13     18   S   0 10                                                                              0  0                                                                              100                                                                               0                                                                              90 30  0 40                                                                               0  0  0 10 0  10                Cmpd 13     18   WB  0 10                                                                              0  0                                                                               0 20                                                                               0  0  0 20                                                                               0 20  0  0 0   0                Cmpd 13     18   S   0 10                                                                              0  0                                                                              100                                                                              40                                                                              90 60 50 30                                                                               0  0  0  0 0  10                VC           0   WB  0 10                                                                              0 10                                                                               0 10                                                                               0 10  0  0                                                                               0 10  0  0 0   0                VC           0   S   0  0                                                                              0 10                                                                               0  0    0  0 10                                                                               0  0  0  0 0   0                __________________________________________________________________________     WB = whole blood                                                              S = serum                                                                

                                      TABLE 23C                                   __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 48 hr in vitro Exposure                                                                  Day 30  5     Day   Day   Day   Day   Day                            Dose Blood                                                                             0   Min Hr    1     2     3     4     5                  Treatment   mg/kg                                                                              Sample                                                                            L A L A L  A  L  A  L  A  L  A  L  A  L A                __________________________________________________________________________    Cmpd 13 + oxfendazole                                                                     18 + 10                                                                            WB  0 10                                                                              0 30                                                                               0 50 40 90 30 80 40 80  0 40 0 10               Cmpd 13 + oxfendazole                                                                     18 + 10                                                                            S   0 30                                                                              0 30                                                                               80                                                                              90 100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              0 50               Cmpd 13 + oxfendazole                                                                     18 + 10                                                                            WB  0 30                                                                              0 40                                                                               0 30 90 90 90 90 40 80  0 30 0 10               Cmpd 13 + oxfendazole                                                                     18 + 10                                                                            S   0 10                                                                              0 10                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              90 100                                                                              90 0 30               Cmpd 13     18   WB  0 20                                                                              0 10                                                                               0 10  0 40  0 10  0 10  0 10 0 10               Cmpd 13     18   S   0 10                                                                              0  0                                                                              100                                                                              80 100                                                                              100                                                                               0 50  0 40  0 10 0 20               Cmpd 13     18   WB  0 20                                                                              0 20                                                                               0 30  0  0  0 30  0 70  0 10 0 10               Cmpd 13     18   S   0 20                                                                              0 20                                                                              100                                                                              80 100                                                                              100                                                                              60 80  0 50  0 20 0 20               VC           0   WB  0 20                                                                              0 20                                                                               0 30  0 10  0 20  0 20  0  0 0 20               VC           0   S   0 10                                                                              0 30                                                                               0 10  0 10  0 30  0 10  0 10 0 10               __________________________________________________________________________

                                      TABLE 24A                                   __________________________________________________________________________    Test 24: Evaluation in Cattle of 1,5-bis(4-(trifluoromethylphenyl)-3-forma    zancarbonitrile                                                               trimethyloctadecylammonium salt (Cmpd 13), Administered Intraruminally,       Formulation S                                                                 Helminthologic Data                                                           Worm Eggs Per Gram of Feces (EPG)                                                                          % Worm Total                                     Dose     Days Following Treatment                                                                          Egg    Worm  % Worm                              mg/kg                                                                              Pre*                                                                              1   2   3   4   5-7*                                                                              Reduction                                                                            Counts.sup.1                                                                        Reduction                           __________________________________________________________________________    18   267  0   0   0   0   0  100    64**  73.8                                18    67  0   0   0   0   0  100    17**  93.0                                VC   167 300 300 400 300 225  0     244   0                                   __________________________________________________________________________     *Average of 3 days sampling                                                   **Ova appeared nonviable. Female worms had only 6-8 eggs in utero and wer     granular and unsegmented.                                                     .sup.1 At necropsy 7 days following treatment                            

                                      TABLE 24B                                   __________________________________________________________________________    Percent Insecticidal Activity against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 24 hr in vitro Exposure                                             Dose                                                                              Day 0 30 Min                                                                              5 Hr  Day 1  Day 2 Day 3 Day 4 Day 5   Day 6                  mg/kg                                                                             L  A  L  A  L  A  L   A  L  A  L  A  L  A  L   A   L   A                  __________________________________________________________________________    18  0   0 0  0  0  10  25 20 0  40 0  10 0   0 0   0   0    0                 18  0  20 0  0  0  10 100 70 0   0 0   0 0  10 0   0   0    0                 VC  0  10 0  0  0  20  0   0 0  10 0   0 0  10 0   0   0   10                 __________________________________________________________________________

                                      TABLE 24C                                   __________________________________________________________________________    Percent Insecticidal Activity against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 48 hr in vitro Exposure                                             Dose Day 0 30 Min                                                                              5 Hr  Day 1   Day 2 Day 3 Day 4 Day 5 Day 6                  mg/kg                                                                              L  A  L  A  L  A  L   A   L  A  L  A  L  A  L  A  L   A                  __________________________________________________________________________    18   0  30 0  30 0  40  90 100 60 80 0  30 0  20 0  20 0   10                 18   0  20 0  30 0  60 100 100  0 50 0   0 0  30 0  10 0   20                 VC   0  20 0  20 0  30  0   10  0 30 0  20 0  10 0  30 0   10                 __________________________________________________________________________

                                      TABLE 25A                                   __________________________________________________________________________    Test 25: Evaluation in Cattle of 1,5-bis(4-(trifluoromethylphenyl)-3-forma    zancarbonitrile                                                               trimethyloctadecylammonium salt (Cmpd 13), Administered Intraruminally as     an Emulsion.sup.2                                                             Helminthologic Data                                                           Worm Eggs Per Gram of Feces (EPG)                                                                              % Worm Total                                 Dose     Days Following Treatment                                                                              Egg    Worm                                  mg/kg                                                                              Pre*                                                                              1   2   3   4   5-7*                                                                              10  Reduction                                                                            Counts.sup.1                          __________________________________________________________________________    18   550 500  800                                                                               600                                                                              600 800 800 0      ND                                    18   750 600 1200                                                                              1750                                                                              900 750 800 0      ND                                    36   500 600  900                                                                              1000                                                                              700 650 500 0      ND                                    36   750 700 1100                                                                               600                                                                              500 400 400 46.7   ND                                    VC   350 500  600                                                                               800                                                                              600 500 400 0      ND                                    __________________________________________________________________________     *Average of 3 days sampling                                                   .sup.1 At necropsy 10 days following treatment                                .sup.2 Formulation T diluted 1:1 with distilled water                         ND = not determined                                                      

                                      TABLE 25B                                   __________________________________________________________________________    Percent Insecticidal Activity against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 24 hr in vitro Exposure                                             Dose  Day 0 30 Min                                                                              5 Hr   Day 1   Day 2 Day 3 Day 4 Day 5 Day 6                mg/kg L  A  L  A  L   A  L   A   L  A  L  A  L  A  L  A  L  A                 __________________________________________________________________________    18    0  30 0  30  10 30 100 20  0  30 0  10 0  10 0  10 0  40                18    0  20 0  10  10  0 100 100 0  40 0  10 0  50 0  30 0  10                36    0  20 0  20 100 50 100 90  90 60 0  20 0  30 0  10 0  20                36    0  30 0  40 100 20 100 40  0    0                                                                              0   0 0  40 0  30 0  10                VC    0  50 0  30  0   0  0  20  0  30 0   0 0  20 0  60 0  10                __________________________________________________________________________

                                      TABLE 25C                                   __________________________________________________________________________    Percent Insecticidal Activity against Phormia regina ("L") and Stomoxys       calcitrans ("A")                                                              Following 48 hr in vitro Exposure                                             Dose                                                                              Day 0 30 Min                                                                              5 Hr    Day 1   Day 2   Day 3 Day 4 Day 5 Day 6               mg/kg                                                                             L  A  L  A  L   A   L   A   L   A   L  A  L  A  L  A  L  A                __________________________________________________________________________    18  0  40 0  40  90 100 100 100  0   80 0  70 0  20 0  40 0  50               18  0  30 0  10  90 80  100 100 100 100 0  40 0  50 0  40 0  20               36  0  40 0  30 100 90  100 100 100 100 0  50 0  50 0  40 0  30               36  0  30 0  50 100 80  100 100  10  80 0   0 0  50 0  40 0  10               VC  0  90 0  60  0  10   0   30  0   60 0   0 0  30 0  70 0  30               __________________________________________________________________________

TESTS 26 AND 27 Trials against face fly (Musca autumnalis), horn fly(Haematobia irritans), and stable fly (Stomoxys calcitrans)

1,5-Bis(4-trifluoromethyl)phenyl)-3-formazancarbonitriletrimethyloctadecylammonium salt was evaluated in heifers against

face fly, Musca autumnalis

horn fly, Haematobia irritans

stable fly, Stomoxys calcitrans

Two trials were conducted with the same heifers, two per treatment groupand four groups. In the first trial, the compound was employed at ratesof 9, 13.5 or 18 mg/kg of the compound; the fourth group received avehicle control. In the second trial, the compound was employed at 27.0or 36.0 mg/kg, and the two remaining groups received no treatment(control) and vehicle only (vehicle control). Formulation O wasutilized. It and vehicle control were administered by intraruminalinjection.

In both trials, various tests were employed to determine efficacy. Feceswere collected and bioassayed for activity against first instar face flyand horn fly larvae. Adult horn flies and stable flies were introducedto the heifers and effects noted. Finally, blood was collected and boththe blood and serum portion bioassayed against stable flies.

The results observed were as follows. The emergence of face fly and hornfly adults from feces collected 1 and 2 days after treatment wascompletely inhibited. Populations of adult horn flies feeding on theheifers were reduced at 27 mg/kg; populations of stable flies were notaffected. Blood and serum bioassays likewise showed control, especiallyat the higher doses.

TEST 28 Test against ovine lungworm (Dictvocaulus filaria)

1,5-Bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitriletrimethyloctadecylammonium salt was evaluated for the control of ovinelungworm, Dictyocaulus filaria in sheep. The compound, formulated asFormulation U, was administered by intraruminal injection to sheep whichhad previously been inoculated with lungworm larvae. The doses employedwere 9, 18, or 36 mg/kg. A fourth group of sheep received only vehicle.Fecal samples were collected over a 7 to 9-day period followingtreatment, and the sheep were then euthanized and residual lungwormscounted.

The results indicated efficacy of the compound against lungworm. Theworm counts at necropsy showed reductions of 5.3%, 59.8% and 61.2%, atthe three respective dose levels of the compound. Lungworm larval outputin the feces was lower in the 18 and 36 mg/kg treatment groups.

TEST 29 Test against horn fly (Haematobia irritans), and stable fly(Stomoxys calcitrans)

1,5-Bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitriletrimethyloctadecylammonium salt was evaluated for the control of hornflies, Haematobia irritans and stable flies, Stomoxys calcitrans on beefcattle. Eight animals were used, two per treatment group. The treatmentswere 18, 27, or 36 mg/kg of the compound or vehicle control. Theformulation used was Formulation Q. The effect on horn flies wasevaluated by releasing the flies on to the animals and determiningmortality. The effect on stable flies was determined by allowing cagedflies to feed on the cattle periodically. Feces were also collected andassayed against horn flies.

Horn flies fed on cattle on day 1 were significantly affected. Treatmentinduced mortality was 72, 95 and 86% for the 18, 27, and 36 mg/kg levelsof compound, respectively. The number of surviving horn flies was lowerin all treatments than in the controls on days 2 to 5. There was almostno effect of the treatments on stable flies fed only once on treatedanimals. Mortality produced in stable flies fed four times on thetreated animals was statistically higher than mortality measured foreither single or double fed flies for all three dosage levels. Noimmature horn flies emerged from fly seeded manure collected during thesecond day after treatment for all treatment levels. No flies emergedfrom manure collected from the 27 and 36 mg/kg levels on day 3 followingtreatment. This study demonstrated that intraruminal applications of thecompound in cattle resulted in systemic transport of the drug or itsmetabolites in the treated animals.

TESTS 30 AND 31 Tests against the Atwood (ivermectin-resistant) strainof Haemonchus contortus in Sheep

In a first test,1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitriletrimethyloctadecylammonium salt (Compound 13) was evaluated in lambs forthe control of the Atwood (ivermectin-resistant) strain of Haemonchuscontortus. There were two lambs per group and three groups. One groupreceived the compound under evaluation at 36 mg/kg, Formulation R; thesecond group received the corresponding vehicle; and the third groupreceived ivermectin at 0.2 mg/kg. The subject compound and the vehiclewere each administered by a single intraruminal injection. Theivermectin was administered orally.

The lambs were maintained for seven days, then euthanized and theabomasa recovered and counts made. Feces were also collected and eggcounts made. Results were as described in the following table.

                                      TABLE 26A                                   __________________________________________________________________________    Egg/gm counts and nematode recovery from the abomasa of lambs with            Atwood                                                                        strain Haemonchus contortus                                                           Egg/gm in Feces (day)                                                              3 days post                                                                           7 days post                                                                           Haemonchus                                                                              Trichostrongylus                       Treatment                                                                             0    treatment                                                                             treatment                                                                             Male                                                                              Female                                                                              Male                                                                              Female                             __________________________________________________________________________    Vehicle 2450 2900    1800    660 500   13  80                                 Control 4200 4100    4050    433 600   40  73                                 Ivermectin                                                                            1550 3150    3500    647 633    0   0                                         7750 4250    4600    733 833    0   0                                 Cmpd 13 3750   0       0      0   0    13  53                                         3350   0       0      0   0     0   0                                 __________________________________________________________________________

A followup study was done, with five animals per treatment group, andemploying both ivermectin-susceptible and ivermectin-resistant strainsof Haemonchus contortus. Ivermectin was included as a reference.Compound 13 was administered by intraruminal injection; ivermectin wasadministered per the product directions. The results were as set forthin the following table.

                                      TABLE 26B                                   __________________________________________________________________________    Helminthologic Data Collected From Sheep Infected With Ivermectin-Suscepti    ble                                                                           or Resistant Haemonchus contortus and Treated With Compound 13 or             Ivermectin                                                                                                                      Necropsy Worm Counts                                        Eggs per   %      Mean                               No. Sheep &    Dose      Gram of Feces                                                                            Reduction                                                                            Total % Worm                Test Group                                                                           Parasite Type                                                                         Treatment                                                                            mg/kg                                                                              Route                                                                              Pre  Day 7 EPG    Worms Reduction             __________________________________________________________________________    1      5 SUS   Cmpd 13                                                                              2.25 IR   2080 3300  0      1013  22                    2      5 RES   "      2.25 IR   1430 2110  0      1200    1.2                 3      5 SUS   "      4.5  IR   3070 1620  47      847  35                    4      5 RES   "      4.5  IR   1600 1730  0       695  43                    5      5 SUS   "      9    IR   2030 1870  7.8     407  69                    6      5 RES   "      9    IR    950  240  75      50   96                    7      5 SUS   Ivermectin                                                                           0.2  Oral 1590   0   100      5     99.6                8      5 RES   Ivermectin                                                                           0.2  Oral   960                                                                              1560  0       460   62*                  9      5 SUS   VC     0    IR   2940 2720  7.5    1303   0                    10     5 RES   VC     0    IR   4450 2780  37.5   1215   0                    __________________________________________________________________________     IR = intraruminal                                                             SUS = ivermectinsusceptible Haemonchus                                        RES = ivermectinresistant Haemonchus                                          *indicating that the resistant trait may be weakening                    

TEST 32 Test against ticks in cattle

1,5-Bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile was evaluated,alone and in combination with oxfendazole, in cattle for the control ofticks (Amblyomma maculatum and Dermacentor variabilis). The dose was 18or 36 mg/kg. Administration was by intraruminal injection, usingFormulation R; oxfendazole was also administered by a separateintraruminal injection. Eight heifers weighing between 180 and 222 kgwere employed, allotted to four treatment groups. Each was infected ondays -2, 0, 1, 2, and 4, with unfed ticks of both species. The tickswere retained in compartments attached to the bodies of the animals.

Blood samples were taken prior to treatment and daily thereafter, andanalyzed by the same in vitro bioassay reported above for larval blowfly and adult stable fly. In general, all dosages of1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile were active inthe 48 hour blood sample following 48 hours in vitro exposure. Thehigher dose (36 mg/kg) was active for 3 days. For blood samples fromanimals treated with both1,5-bis(4-(trifluromethyl)phenyl)-3-formazancarbonitrile andoxfendazole, activity in this bioassay was extended to 5 days followingtreatment. The animals were also observed for the effect on the ticks.Results at day 35 showed modest control of ticks, as reported in thefollowing tables.

                  TABLE 27                                                        ______________________________________                                        Percent of Ticks Replete and Ovipositing                                      TABLE 27A                                                                     Activity in Calves                                                            Infested With Amblyomma americanum Ticks.                                                                             %                                                               No.    %      Replete                                       No.      No.      Ticks  Collected                                                                            Ticks                                         Ticks    Ticks    ovi-   Ticks  Ovi-                                  Treatment                                                                             Collected                                                                              Replete  positing                                                                             Replete                                                                              positing                              ______________________________________                                        VC      30       17       16     57     88                                    Cmpd 13 31       14       2      45     14                                    18 mg/kg                                                                      Cmpd 13 26       14       4      54     29                                    36 mg/kg                                                                      Cmpd 13 29        4       2      14     50                                    36 mg/                                                                        kg +                                                                          oxfendazole                                                                   10 mg/kg                                                                      ______________________________________                                    

                  TABLE 27B                                                       ______________________________________                                        Activity in Calves Infested With Dermacentor variabilis Ticks.                                                        %                                                               No.    %      Replete                                       No.      No.      Ticks  Collected                                                                            Ticks                                         Ticks    Ticks    ovi-   Ticks  Ovi-                                  Treatment                                                                             Collected                                                                              Replete  positing                                                                             Replete                                                                              positing                              ______________________________________                                        VC      32       22       10     69     45                                    Cmpd 13 36       34       16     94     47                                    18 mg/kg                                                                      Cmpd 13 37       29       11     78     38                                    36 mg/kg                                                                      Cmpd 13 33       21        6     64     29                                    36 mg/                                                                        kg +                                                                          oxfendazole                                                                   10 mg/kg                                                                      ______________________________________                                    

TEST 33 Test against common scabies mite in cattle

1,5-Bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile (Compound 13)was evaluated in cattle, alone and in combination with oxfendazole, forthe control of common scabies mite (Psoroptes ovis). Twelve heifersweighing between 179 and 239 kg were employed, allocated to fourtreatment groups. Administration was by intraruminal injection, at dosesof 18 and 36 mg/kg; oxfendazole was administered by a separateintraruminal injection, at a dose of 10 mg/kg.

The animals were infested by placing onto the withers area a scraping ofhair and epidermal matter from a donor animal. To determine the efficacyof treatment, two one-inch square areas were scraped, and the collectedhair and mites evaluated for the number of mites. The mite counts wereas reported in the following table.

                                      TABLE 28                                    __________________________________________________________________________    Activity Against Common Scabies Mite                                                 Dose                                                                   Treatment                                                                            mg/kg        Day-1                                                                             Day 2 Day 4                                                                              Day 7 Day 14                                                                             Day 21                                                                              Day                                                                                Day                  __________________________________________________________________________                                                             35                   VC      0   Avg. No. of                                                                           156 93.33 145  244.33                                                                              211.66                                                                             214.33                                                                              195.5                                                                              176.5                            Mites                                                             Cmpd 13                                                                              18   Avg. No. of                                                                           102.33                                                                            57.33 38.33                                                                              82.33 126.66                                                                             96.33 121.66                                                                             58.5                             Mites                                                                         % Control   38.57%                                                                              73.56%                                                                             66.30%                                                                              40.15%                                                                             55.05%                                                                              37.76%                                                                             66.85%               Cmpd 13                                                                              36   Avg. No. of                                                                           103.33                                                                            124.33                                                                              68.66                                                                              165.66                                                                              421.33                                                                             252.66                                                                              353.66                                                                             175.33                           Mites                                                                         % Control   0%    52.64%                                                                             32.19%                                                                              0%   0%    0%   0.66%                Cmpd 13 +                                                                            36 + 10                                                                            Avg. No. of                                                                           81  28    9.66 7.66  6.33 32.33 38.66                                                                              150                  oxfendazole Mites                                                                         % Control   69.99%                                                                              93.56%                                                                             96.86%                                                                              97.0%                                                                              84.91%                                                                              80.22%                                                                             15.01%               __________________________________________________________________________

TEST 34 Test against fleas and ticks in dogs

1,5-Bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile, as itstetramethylammonium salt (Compound 8) and trimethyloctadecylammoniumsalt (Compound 13) was evaluated for the control of fleas(Ctenocephalides felis ) and ticks (Rhipicephalus sanguineus ) in beagledogs. Twelve dogs, averaging 11.8 kg and infested with fleas, wereallocated to four treatment groups: vehicle control, Compound 8 at 24mg/kg, Compound 13 at 36 mg/kg, and Compound 13 at 36 mg/kg plusoxfendazole at 10 mg/kg. The vehicle control and Compounds 8 and 13 wereadministered by oral capsule (Formulation W); oxfendazole wasadministered by liquid gavage. Reinfestations were done at day 5 forfleas and at days 3 and 6 for ticks. The number of fleas and ticks wasaveraged for each group. Percent control of fleas and ticks was rated intwo ways: by reference to the beginning population in the same treatmentgroup and, for groups receiving a formazan, by reference to thepopulation in the control group on the same day.

Results were as set forth in the following tables.

                  TABLE 29A                                                       ______________________________________                                        Activity against Fleas                                                                     Number of Fleas                                                                     Day    Day   Day   Day   Day                               Treatment                                                                             Dose mg/kg 0      1     3     6     8                                 ______________________________________                                        VC       0         86     79    75    91.7  78.7                                      % Reduction                                                                              --     8.1   12.7  -6.6   8.4                                      from Day 0                                                            Cmpd 8  24         90     11.3  2     49.3  29.3                                      % Reduction                                                                              --     87.4  97.7  45.2  67.4                                      from Day 0                                                                    % Reduction                                                                              --     85.7  97.3  46.2  62.8                                      from Control                                                          Cmpd 13 36         91.7   17    0     33.3  20.3                                      % Reduction                                                                              --     81.5  100   63.7  77.8                                      from Day 0                                                                    % Reduction                                                                              --     80.2  100   63.7  74.2                                      from Control                                                          Cmpd 13/                                                                              36/10      85.3   --    0     18.3   8.3                              oxfendazole                                                                           % Reduction                                                                              --     100   100   78.5  90.3                                      from Day 0                                                                    % Reduction                                                                              --     100   100   80    89.5                                      from Control                                                          ______________________________________                                    

                  TABLE 29B                                                       ______________________________________                                        Activity against Ticks                                                                    Number of Ticks                                                   Treat-            Day    Day  Day  Day    Day                                 ment   Dose mg/kg 0      1    3    6      8                                   ______________________________________                                        VC      0         13.7   13.7 13.3 21     20                                         % Reduction                                                                              --     0    2.9  -53    -45                                        from Day 0                                                             Cmpd 8 24         18     4    2    14     13                                         % Reduction                                                                              --     77.7 88.8 22.2   27.7                                       from Day 0                                                                    % Reduction                                                                              --     70.8 85   33.3   35                                         from Control                                                           Cmpd 13                                                                              36         17     8.3  4    17     13.6                                       % Reduction                                                                              --     51.1 95.6 0      20                                         from Day 0                                                                    % Reduction                                                                              --     39.4 69.9 19     32                                         from Control                                                           Cmpd   36/10      13     2.7  0.67 17.6   14.3                                13/    % Reduction                                                                              --     79.2 94.8 -35.3  -10                                 oxfen- from Day 0                                                             dazole % Reduction                                                                              --     80.3 94.9 10     28.5                                       from Control                                                           ______________________________________                                    

TEST 35 Test against multiple parasites in sheep

1,5-Bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile was evaluatedfor the control of Haemonchus contortus, Ostertagia spp.,Trichostrongylus colubriformis and others in sheep. The compound wasadministered daily for six continuous days, as an oral drench. Theformulation employed was an aqueous suspension. The control sheep weredosed daily with 10 ml of an aqueous suspension (vehicle lackingformazan).

The tapeworm population was reduced by 50% and the Nematodirus spathigerpopulation was reduced 72.3%. Results of other parasites were as setforth in the following tables.

                                      TABLE 30A                                   __________________________________________________________________________    Haemonchus contortus Worm Eggs Per Gram of Feces in Sheep                     Treated by Single Oral Drench of 2.5 mg/kg Bodyweight for Six Days            Using Compound 6 in Aqueous Suspension                                                     Worm Eggs Per Gram of Feces  % Worm Total                               Dose       Days Following Treatment                                                                              Egg    Worm                         Treatment                                                                            mg/kg Pre  1    2   3   4   5-8*                                                                              12 Reduction                                                                            Counts.sup.1                 __________________________________________________________________________    Cmpd 6 2.5 × 6                                                                       11550                                                                              13200                                                                               700                                                                                0   0   0 -- 100    0                                   2.5 × 6                                                                        8100                                                                               7100                                                                               200                                                                                0   0   0 -- 100    0                                   2.6 × 6                                                                       15900                                                                              14500                                                                              1600                                                                                0   0   0 -- 100    0                                   2.5 × 6                                                                       10700                                                                              10700                                                                              1000                                                                                0   0   0 -- 100    0                                   2.5 × 6                                                                        7800                                                                               8100                                                                                0    0                                                                                0   0 -- 100    0                                   2.5 × 6                                                                        3050                                                                               3100                                                                                0   0   0   0 -- 100    0                                                                      Avg 100                                                                              Avg 0                        VC     0      4850                                                                               5300                                                                              4100                                                                              3900                                                                              4300                                                                              4325                                                                              --  0     4155                                0     11800                                                                               9400                                                                              8400                                                                              7700                                                                              7800                                                                              7325                                                                              -- 38     3782                                0     11400                                                                              11600                                                                              9700                                                                              8700                                                                              7600                                                                              7825                                                                              -- 31     3172                                0      2800                                                                               2300                                                                              4700                                                                              4200                                                                              4100                                                                              4450                                                                              --  0     2145                                                                   Avg 17.25                                                                            Avg 3313.5                   __________________________________________________________________________     *Average of 4 days sampling                                                   .sup.1 At necropsy 6 days following treatment                            

                                      TABLE 30B                                   __________________________________________________________________________    Trichostrongyle Worm Eggs Per Gram of Feces in Sheep                          Treated by Single Oral Drench of 2.5 mg/kg Bodyweight for Six Days            Using Compound 6 in Aqueous Suspension                                                     Worm Eggs Per Gram of Feces                                                                              % Worm Total                                 Dose      Days Following Treatment                                                                             Egg    Worm                           Treatment                                                                            mg/kg Pre 1   2   3   4   5-8*                                                                              12 Reduction                                                                            Counts.sup.1                   __________________________________________________________________________    Cmpd 6 2.5 × 6                                                                       1750                                                                              1600                                                                              1400                                                                               700                                                                               600                                                                              300 -- 83     218                                   2.5 × 6                                                                       1000                                                                               900                                                                               600                                                                              1000                                                                               500                                                                              400 -- 60     211                                   2.5 × 6                                                                       1850                                                                              1600                                                                              1400                                                                              1900                                                                              1100                                                                              900 -- 51     348                                   2.5 × 6                                                                       1150                                                                              1300                                                                              1500                                                                              1400                                                                              1300                                                                              950 -- 17     305                                   2.5 × 6                                                                        850                                                                              1000                                                                               600                                                                               500                                                                               500                                                                              300 -- 65      58                                   2.5 × 6                                                                        650                                                                               500                                                                               200                                                                               400                                                                               400                                                                              300 -- 54      71                                                                    Avg 55 Avg 201.8                      VC     0      450                                                                               700                                                                               500                                                                               600                                                                               700                                                                              675 --  0     466                                   0     1100                                                                               800                                                                               600                                                                               600                                                                               800                                                                              825 -- 25     113                                   0     1150                                                                              1200                                                                              1100                                                                              1400                                                                              1200                                                                              1275                                                                              --  0     177                                   0      800                                                                               500                                                                               900                                                                               900                                                                              1000                                                                              1000                                                                              --  0     281                                                                    Avg 6.25                                                                             Avg 259.3                      __________________________________________________________________________     *Average of 4 days sampling                                                   .sup.1 At necropsy 6 days following treatment                            

                                      TABLE 30C                                   __________________________________________________________________________    Helminthologic Data Collected from Sheep Treated by Oral Drench               Formulation of 2.5 mg Compound 6 per kg Each Day for Six Days                           Worm Eggs Per Gram        Average Worm Counts at Necropsy           No.       Haemonchus   Trichostrongyles                                                                           Abomasum          Sm. Intestine           Treatment                                                                           Sheep                                                                             Pre 7 Days                                                                            % Red                                                                              Pre 7 Days                                                                            % Red                                                                              HC  % Red                                                                              Ost % Red                                                                              Tr  %                   __________________________________________________________________________                                                              Red                 Cmpd 6                                                                              6   9517                                                                                0 100  1100                                                                              525 52.3   0 100  137 8.6  201.8                                                                             22.2                VC    4   5056                                                                              5981                                                                               0    875                                                                              944 0    3314                                                                              --   150 --   259.3                                                                             --                  __________________________________________________________________________     HC = Haemonchus                                                               Ost = Ostertagia                                                              Tr = Trichostrongylus                                                         Red = Reduction                                                          

TEST 36 Test against multiple parasites in sheep

Compounds 6, 8, and 13 were evaluated in sheep for the control ofmultiple parasites: Haemonchus contortus, Trichostrongyluscolubriformis, Ostertagia spp., and Monezia expensa (tape worm). Therewere four animals per treatment group. Administration was by oral gavageof an aqueous suspension of the respective compound. Compound dosing wasat amounts equivalent to 5 mg/kg of the parent compound, Compound 6. Thetest was continued for ten days, at which time the animals wereeuthanized and internal worm counts made.

Activity was determined by egg count per gram of feces, in vitro assayof serum samples, and worm counts in the abomasum and small intestine atnecropsy. Results were as set forth in the following tables.

                                      TABLE 31A                                   __________________________________________________________________________    Haemonchus contortus Worm Eggs Per Gram of Feces in Sheep                     Treated by an Oral Gavage of Compound 6 and Salts in Aqueous Suspension                       Worm Eggs Per Gram of Feces                                                                              % Worm Total                       Rx         Dose      Days Following Treatment                                                                            Egg    Worm  % Worm                No. Treatment                                                                            mg/kg                                                                              Pre* 1   2    3   4   5-7* Reduction                                                                            Counts.sup.1                                                                        Reduction             __________________________________________________________________________    1   Cmpd 6 5     633  800                                                                               0     0   0   0  100     0    100                              5    1000 1300                                                                               0     0   0   0  100     0    100                              5    1600  800                                                                              100    0   0   0  100     0    100                              5    3833 2700                                                                               0     0   0   0  100     0    100                   2   Cmpd 8 6     733  200                                                                               0     0   0   0  100     13**   97.6                           6     400   0  0     0   0   0  100     0    100                              6    1767 1000                                                                              100    0   0   0  100     0    100                              6      0    0  0     0   0 --   --      0    --                    3   Cmpd 13                                                                              9      0    0  0     0   0   0  --     --    --                               9    1200  300                                                                               0     0   0   0  100    18      96.6*                          9     700  100                                                                               0     0   0   0  100     0    100                              9    3067  900                                                                              300    0   0   0  100     0    100                   4   VC     0    1867 1900                                                                              2600 2800                                                                              2400                                                                              2400  0     441   --                        VC     0    1500 3100                                                                              2400 2200                                                                              2300                                                                              2300  0     626   --                    __________________________________________________________________________     *Average of 2 days sampling                                                   .sup.1 At necropsy 7 days following treatment                                 **very small immature                                                    

                                      TABLE 31B                                   __________________________________________________________________________    Trichostrongyle Worm Eggs Per Gram of Feces in Sheep                          Treated by an Oral Gavage of Compound 6 and Salts in Aqueous Suspension                       Worm Eggs Per Gram of Feces                                                                             % Worm                              Rx         Dose      Days Following Treatment                                                                           Egg                                 No. Treatment                                                                            mg/kg                                                                              Pre* 1    2   3   4   5-7*                                                                              Reduction                           __________________________________________________________________________    1   Cmpd 6 5    300  500  100  0   0  200 33                                             5    867  900  400 600 500 450 48                                             5     0    0    0   0   0   0  --                                             5    2300 900  800 900 700 700 70                                  2   Cmpd 8 6    367  200  200 300 100 300 19                                             6    200  300  700 200 300 300  0                                             6    1167 700  300 300 200 150 87                                             6    500  800  400 300 500 450 10                                  3   Cmpd 13                                                                              9    300  300  200 200 100 100 67                                             9    667  100   0   0    0 150 78                                             9     0    0    0   0   0   0  --                                             9    833  400  300 100 400 650 22                                  4   VC     0    833  600  900 700 600 800  4                                      VC     0    433  1300 900 800 700 650  0                                  __________________________________________________________________________     *Average of 2 days sampling                                              

                                      TABLE 31C                                   __________________________________________________________________________    Summary and Necropsy Data - Helminthologic Data Collected from Sheep          Treated                                                                       With Oral Drench Formulations of Compound 6 and Salts in Aqueous              Suspension                                                                              Worm Eggs Per Gram       Average Worm Counts at Necropsy            No.       Haemonchus  Trichostrongyles                                                                           Abomasum           Sm. Intestine           Treatment                                                                           Sheep                                                                             Pre                                                                              7 Days                                                                             % Red                                                                             Pre 7 Days                                                                            % Red                                                                              HC   % Red                                                                              Ost % Red                                                                              Tr  %                   __________________________________________________________________________                                                              Red                 Cmpd 6                                                                              4   1767                                                                               0  100 1156                                                                              450 61   0    100  101 73   21  89                  Cmpd 8                                                                              3    967                                                                               0  100  559                                                                              300 46     4.3*                                                                             99.2  80 79   42  79                  Cmpd 13                                                                             3   1656                                                                               0  100  600                                                                              300 50    6*  99    47 87   86  57                  VC    2   1684                                                                             2350  0   633                                                                              725  0   534  --   373 --   198 --                  __________________________________________________________________________     *immature stages                                                              HC = Haemonchus                                                               Ost =  Ostertagia                                                             Tr = Trichostrongylus                                                         Red = Reduction                                                          

                                      TABLE 31D                                   __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina Following 24 hr in       vitro Exposure                                                                       Dose                                                                   Treatment                                                                            mg/kg                                                                             Pre 1 HR                                                                              4 HR 8 HR                                                                              12 HR                                                                              24 HR                                                                              36 HR                                                                              Day 2                                                                              Day 3                                                                              Day                                                                                Day                 __________________________________________________________________________                                                              5                   Cmpd 6 5.0 0    0  100  100 100  100   0    0   0    0    0                          5.0 0    0  100  100 100  100  100   0   0    0    0                          5.0 0   100 100  100 100  100  100   0   0    0    0                          5.0 0    0  100  100 100  100   80   0   0    0    0                   Cmpd 8 6.0 0    0  100  100 100  100  100   0   0    0    0                          6.0 0   100 100  100 100  100  100   0   0    0    0                          6.0 0   100 100  100 100  100  100   0   0    0    0                          6.0 0   100 100  100 100  100  100  10   0    0    0                   Cmpd 13                                                                              9.0 0    0  100  100 100  100  100  100  0    0    0                          9.0 0    0  100  100 100  100  100  100  0    0    0                          9.0 0   100 100  100 100  100  100  100  0    0    0                          9.0 0   100 100  100 100  100  100   0   0    0    0                   VC     0   0    0   0    0   0    0    0    0   0    0    0                   VC     0   0    0   0    0   0    0    0    0   0    0    0                   __________________________________________________________________________

                                      TABLE 31E                                   __________________________________________________________________________    Percent Insecticidal Activity Against Phormia regina Following 48 hr in       vitro Exposure                                                                       Dose                                                                   Treatment                                                                            mg/kg                                                                             Pre 1 HR                                                                              4 HR 8 HR                                                                              12 HR                                                                              24 HR                                                                              36 HR                                                                              Day 2                                                                              Day 3                                                                              Day                                                                                Day                 __________________________________________________________________________                                                              5                   Cmpd 6 5.0 0    0  100  100 100  100   50   0   0    0    0                          5.0 0    0  100  100 100  100  100   0   0    0    0                          5.0 0   100 100  100 100  100  100   0   0    0    0                          5.0 0    0  100  100 100  100   95   0   0    0    0                   Cmpd 8 6.0 0    0  100  100 100  100  100   0   0    0    0                          6.0 0   100 100  100 100  100  100   0   0    0    0                          6.0 0   100 100  100 100  100  100   0   0    0    0                          6.0 0   100 100  100 100  100  100  90   0    0    0                   Cmpd 13                                                                              9.0 0    0  100  100 100  100  100  100  0    0    0                          9.0 0    0  100  100 100  100  100  100  40   0    0                          9.0 0   100 100  100 100  100  100  100  80   0    0                          9.0 0   100 100  100 100  100  100   0   0    0    0                   VC     0   0    0   0    0   0    0    0    0   0    0    0                   VC     0   0    0   0    0   0    0    0    0   0    0    0                   __________________________________________________________________________

In addition, activity was noted against tapeworms. Tapeworms werecompletely eliminated from two sheep in each of the treatment groupsreceiving Compounds 6 and 8; in the treatment groups receiving Compound13, one of two infected animals was completely cleared of tapeworms andonly eleven immature worms remained in the other.

I claim:
 1. A method for protecting a vertebrate animal against ablood-ingesting parasite or a non-blood-ingesting intestinal parasitewhich comprises administering to the animal an effective amount of anactive agent which is a compound of the formula: ##STR14## wherein eachR independently represents a moiety of the formula: ##STR15## wherein R¹is cyano;R² is nitro; R³ is bromo, chloro, or fluoro; R⁴ is iodo or agroup of the formula --R⁵ _(n) R⁶ wherein n represents 0 or 1, R⁵represents--O--, --S--, --SO--, --SO₂, or --OSO₂ --, and R⁶represents--CF₃, --CF₂ CF₂ H, --CH₂ CF₃, or --C₂ F₅ ;with the followinglimitations: (1) at least one R bears at least one substituent, (2) whenan R contains one or more R¹, R², or R⁴ substituents, the total numberof substituents on that R is not more than 3; or a physiologicallyacceptable salt thereof.
 2. The method of Claim 1 for protecting avertebrate animal against a blood-ingesting parasite.
 3. The method ofClaim 2 wherein the active agent is1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile or aphysiologically acceptable salt thereof.
 4. The method of Claim 3wherein the active agent is1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile.
 5. The methodof Claim 3 wherein the active agent is the levamisole salt of1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile.
 6. The methodof Claim 3 wherein the active agent is a quaternary ammonium salt of1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile of theformula: ##STR16## wherein each R⁷ is independently selected from thegroup consisting of alkyl of from 1 to 20 carbon atoms, with the totalnumber of carbon atoms in all of the R⁷ groups being from 4 to
 40. 7.The method of Claim 6 wherein the active agent is1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitriletetramethylammonium salt.
 8. The method of Claim 6 wherein the activeagent is 1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitriletetraethylammonium salt.
 9. The method of Claim 6 wherein the activeagent is 1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitriletetra-n-propylammonium salt.
 10. The method of claim 6 wherein theactive agent is1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitriletetra-n-butylammonium salt.
 11. The method of claim 6 wherein the activeagent is 1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitriletrimethyloctadecylammonium salt.
 12. The method of claim 2 wherein thevertebrate animal is a fish.
 13. The method of claim 12 wherein theactive agent is1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile or aphysiologically acceptable salt thereof.
 14. The method of claim 2wherein the vertebrate animal is a bird.
 15. The method of claim 14wherein the active agent is1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile or aphysiologically acceptable salt thereof.
 16. The method of claim 2wherein the vertebrate animal is a mammal.
 17. The method of claim 16wherein the active agent is1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile or aphysiologically acceptable salt thereof.
 18. The method of claim 16wherein the mammal is a cow.
 19. The method of claim 18 where the bloodingesting parasite is an Ostertagia species.
 20. The method of claim 19wherein the active agent is1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile or aphysiologically acceptable salt thereof.
 21. The method of claim 16wherein the mammal is a sheep.
 22. The method of claim 21 wherein theblood ingesting parasite is a Haemonchus species.
 23. The method ofclaim 22 wherein the active agent is1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile or aphysiologically acceptable salt thereof.
 24. The method of claim 22wherein the Haemonchus species is an ivermectin-resistant Haemonchusspecies.
 25. The method of claim 24 wherein the active agent is1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile or aphysiologically acceptable salt thereof.
 26. The method of claim 16wherein the vertebrate animal is a cat or dog.
 27. The method of claim26 wherein the blood ingesting parasite is a flea or tick.
 28. Themethod of claim 27 wherein the active agent is1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile or aphysiologically acceptable salt thereof.
 29. The method of claim 1 forprotecting a vertebrate animal against a non-blood-ingesting intestinalparasite.
 30. The method of claim 29 wherein the active agent is1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile or aphysiologically acceptable salt thereof.
 31. A method for inhibiting thegrowth of parasitic organisms in feces of a warm blooded animal whichcomprises administering to the animal an effective amount of an activeagent which is a compound of the formula: ##STR17## wherein each Rindependently represents a moiety of the formula: ##STR18## wherein R¹is cyano;R² is nitro; R³ is bromo, chloro, or fluoro; R⁴ is iodo or agroup of the formula --R⁵ _(n) R⁶ wherein n represents 0 or 1, R⁵represents--O--, --S--, --SO--, --SO₂, or --OSO₂ --, and R⁶represents--CF₃, --CF₂ CF₂ H, --CH₂ CF₃, or --C₂ F₅ ;with the followinglimitations: (1) at least one R bears at least one substituent, (2) whenan R contains one or more R¹, R², or R⁴ substituents, the total numberof substituents on that R is not more than 3; or a physiologicallyacceptable salt thereof.
 32. The method of claim 31 wherein the activeagent is 1,5-bis(4-(trifluromethyl)phenyl)-3-formazancarbonitrile or aphysiologically acceptable salt thereof.
 33. A method for protecting avertebrate animal against a parasite which comprises administering tothe animal both a first active agent which is a compound of the formula:##STR19## wherein each R independently represents a moiety of theformula: ##STR20## wherein R¹ is cyano;R² is nitro; R³ is bromo, chloro,or fluoro; R⁴ is iodo or a group of the formula --R⁵ _(n) R⁶ wherein nrepresents 0 or 1, R⁵ represents--O--, --S--, --SO--, --SO₂, or --OSO₂--, and R⁶ represents--CF₃, --CF₂ CF₂ H, --CH₂ CF₃, or --C₂ F₅ ;with thefollowing limitations: (1) at least one R bears at least onesubstituent, (2) when an R contains one or more R¹, R², or R⁴substituents, the total number of substituents on that R is not morethan 3; or a physiologically acceptable salt thereof; as well as asecond active agent, which is a compound selected from the groupconsisting of albendazole, fenbendazole, flubendazole, mebendazole,oxfendazole, oxibendazole, ricobendazole, thiabendazole,triclavendazole, levamisole, morantel, pyrantel, and piperazine; saidfirst and second active agents being administered in amounts whichtogether are effective to control the parasite.
 34. The method of claim33 wherein the first active agent is1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile or aphysiologically acceptable salt thereof.
 35. The method of claim 34wherein the second active agent is oxfendazole.
 36. The method of claim34 wherein the second active agent is levamisole.
 37. A compound of theformula: ##STR21## wherein each R independently represents a moiety ofthe formula: ##STR22## wherein R¹ is cyano;R² is nitro; R³ is bromo,chloro, or fluoro; R⁴ is iodo or a group of the formula --R^(5a) _(n) R⁶wherein n represents 0 or 1, R^(5a) represents--O--, --S--, --SO--, or--SO₂, and R⁶ represents--CF₃, --CF₂ CF₂ H, --CH₂ CF₃, or --C₂ F₅ ;withthe following limitations: (1) at least one R bears at least onesubstituent, (2) when an R contains one or more R¹, R², or R⁴substituents, the total number of substituents on that R is not morethan 3; and each R⁷ is independently selected from the group consistingof alkyl of from 1 to 20 carbon atoms, with the total number of carbonatoms in all of the R⁷ groups being from 4 to
 40. 38. A compound ofclaim 37 which is any ##STR23## salt of1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile.
 39. Thecompound of claim 38 which is1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitriletetramethylammonium salt.
 40. The compound of claim 38 which is1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitriletetraethylammonium salt.
 41. The compound of claim 38 which is1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitriletetra-n-propylammonium salt.
 42. The compound of claim 38 which is1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitriletetra-n-butylammonium salt.
 43. The compound of claim 38 which is1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitriletetra-n-pentylammonium salt.
 44. The compound of claim 38 which is1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitriletrimethyloctadecylammonium salt.
 45. A compound of the formula:##STR24## wherein each R independently represents a moiety of theformula: ##STR25## wherein R¹ is cyano;R² is nitro; R³ is bromo, chloro,or fluoro; R⁴ is iodo or a group of the formula --R⁵ _(n) R⁶ wherein nrepresents 0 or 1, R⁵ represents--O--, --S--, --SO--, --SO₂, or --OSO₂--, and R⁶ represents--CF₃, --CF₂ CF₂ H, --CH₂ CF₃, or --C₂ F₅ ;with thefollowing limitations: (1) at least one R bears at least onesubstituent, (2) when an R contains one or more R¹, R², or R⁴substituents, the total number of substituents on that R is not morethan 3; and wherein X⁺ is a cation of levamisole, morantel, pyrantel, orpiperazine.
 46. The compound of Claim 45 wherein ##STR26## is the anionfrom 1,5-bis(4-(trifluoromethyl)phenyl)-3-formazancarbonitrile.
 47. Thecompound of Claim 46 wherein X⁺ is a cation from levamisole.
 48. Acompound of the formula ##STR27## wherein each R independentlyrepresents a moiety of the formula: ##STR28## wherein R¹ is cyano;R² isnitro; R³ is bromo, chloro, or fluoro; R⁴ is iodo or a group of theformula --R⁵ _(n) R⁶ wherein n represents 0 or 1, R⁵ represents--O--,--S--, --SO--, --SO₂, or --OSO₂ --, and R⁶ represents--CF₃, --CF₂ CF₂ H,--CH₂ CF₃, or --C₂ F₅ ;with the following limitations: (1) at least oneR bears at least one substituent which is --R⁵ _(n) R⁶ wherein n is 1and R⁵ is --OSO₂ --; (2) when an R contains one or more R¹, R², or R⁴substituents, the total number of substituents on that R is not morethan 3; or a physiologically acceptable salt thereof.
 49. The compoundof Claim 48 which is1,5-bis(4-(trifluoromethylsulfonyloxy)phenyl)-3-formazancarbonitrile ora physiologically acceptable salt thereof.